Therapeutic phenoxyalkylazoles and phenoxyalkylazines

ABSTRACT

Compounds of the formula    &lt;IMAGE&gt;  Formula I  wherein Azo is alkyltetrazolyl or is chosen from the group consisting of oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, triazinyl, thiazolyl, isothiazolyl or any of these substituted with a member of the group consisting of alkyl, alkylthio, alkoxy, hydroxy, halo, cyano, nitro, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkanoyl, fluoroalkyl or the N-oxide of any of the preceding; Y is an alkylene bridge of 3-9 carbon atoms; R1 and R2 are each individually chosen from hydrogen, halo, alkyl, alkenyl, amino, alkylthio, hydroxy, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkoxy, nitro, carboxy, alkoxycarbonyl, dialkylaminoalkyl, alkylaminoalkyl, aminoalkyl, difluoromethyl, trifluoromethyl or cyano; R3 is alkoxycarbonyl, alkyltetrazolyl, phenyl or a heterocycle chosen from benzoxazolyl, benzathiazolyl, thiadiazolyl, imidazolyl, dihydroimidazolyl, oxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, furyl, triazolyl, tetrazolyl, thiophenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or substituted phenylor substituted heterocyclyl wherein the substitution is with alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy, furyl, thienyl or fluoroalkyl; the N-oxide thereof; or a pharmaceutically acceptable acid addition salt thereof is an effective antipicornaviral agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of our prior application Ser. No.08/693,530, filed Aug. 2, 1996, now U.S. Pat. No. 5,721,261, which inturn is a division of our prior application Ser. No. 08/242,752, filedMay 13, 1994, now U.S. Pat. No. 5,552,420, issued Sep. 3, 1996.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

This invention relates to novel heterocyclic substitutedphenoxyalkylazines and phenoxyalkylazoles, to methods of preparationthereof and to methods of use thereof as antipicornaviral agents.

SUMMARY OF THE INVENTION

It has now been found that compounds of Formula I are effectiveantipicornaviral agents. Accordingly, the present invention relates to acompound of the formula ##STR2## wherein Azo is alkyltetrazolyl or ischosen from the group consisting of triazinyl, oxadiazolyl, imidazolyl,triazolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl or any of thesesubstituted with a member of the group consisting of alkyl, alkylthio,alkoxy, hydroxy, halo, cyano, nitro, hydroxyalkyl, alkoxycarbonyl,alkoxyalkyl, alkanoyl, and fluoroalkyl; or the N-oxide of any of thepreceding;

Y is an alkylene bridge of 3-9 carbon atoms;

R₁ and R₂ are each individually chosen from hydrogen, halo, alkyl,alkenyl, amino, alkylthio, hydroxy, hydroxyalkyl, alkoxyalkyl,alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkoxy, nitro,carboxy, alkoxycarbonyl, dialkylaminoalkyl, alkylaminoalkyl, aminoalkyl,difluoromethyl, trifluoromethyl or cyano;

R₃ is alkoxycarbonyl, alkyltetrazolyl, phenyl or a heterocycle chosenfrom benzoxazolyl, benzothiazolyl, thiadiazolyl, imidazolyl,dihydroimidazolyl, oxazolyl, thiazolyl, oxadiazolyl, pyrazolyl,isoxazolyl, isothiazolyl, furyl, triazolyl, thiophenyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl or substituted phenyl or substitutedheterocyclyl wherein the substitution is with alkyl, alkoxyalkyl,cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy, furyl, thienyl orfluoroalkyl is an N-oxide thereof, or a pharmaceutically acceptable acidaddition salt thereof.

The invention also relates to compositions for combating picornavirusescomprising an antipicornavirally effective amount of a compound ofFormula I with a suitable carrier or diluent, and to methods ofcombating picornaviruses therewith, including the systemic treatment ofpicornaviral infections in a mammalian host.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Compounds of Formula I are useful as antipicornaviral agents, and arefurther described hereinbelow.

Alkyl and alkoxy mean aliphatic radicals, including branched radicals,of from one to five carbon atoms. Thus the alkyl moiety of such radicalsinclude, for example methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, t-butyl and pentyl and the like.

Cycloalkyl means an alicyclic radical having from three to seven carbonatoms as illustrated by cyclopropyl, cyclobutyl, cyclopentyl,cycloheptyl, and cyclohexyl; and

Halo means bromo, chloro, iodo or fluoro.

Heterocyclyl or Het refers to a 5 or 6 membered carbon based heterocycleradical, having from one to about four nitrogen atoms and/or one oxygenor sulfur atom, provided that no two oxygen and/or sulfur atoms areadjacent in the heterocycle. Examples of these include furyl, oxazolyl,isoxazolyl, pyrazyl, imidazolyl, thiazolyl, tetrazolyl, thienyl,pyridyl, oxadiazolyl, thiadiazolyl, triazinyl, pyrimidinyl and the like.

The term heterocyclyl includes all known isomeric radicals of thedescribed heterocycles unless otherwise specified, for example,thiadiazolyl encompasses 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-5-yl,and 1,2,4-thiadiazol-3-yl; thiazolyl encompasses 2-thiazolyl,4-thiazolylyl and 5-thiazolyl and the other known variations of knownheterocyclyl radicals. Thus any isomer of a named heterocycle radical iscontemplated. These heterocycle radicals can be attached via anyavailable nitrogen or carbon, for example, tetrazolyl contemplates5-tetrazolyl or tetrazolyl attached via any available nitrogen of thetetrazolyl ring; furyl encompasses furyl attached via any availablecarbon, etc. The preparation of such isomers are well known and wellwithin the scope of skilled artisan in medicinal or organic chemistry.

Certain heterocycles can exist as tautomers, and the compounds asdescribed, while not explicity describing each tautomeric form, aremeant to embrace each and every tautomer. For example, pyridinone andhydroxy pyridine radicals are tautomers. Thus the compounds of formula Idepicted as having hydroxy pyridine radicals as R₃ of the compounds areunderstood to include the tautomeric pyridinones. Any tautomeric form ofany heterocycle is thus also included within the scope of thedescription.

In the use of the terms hydroxyalkyl and alkoxyalkyl, it is understoodthat the hydroxy and alkoxy groups can occur at any available positionof the alkyl. Thus hydroxyalkyl and alkoxyalkyl include, for example,hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl,2-hydroxyisopropyl, 2-, 3-, 4- and 5-hydroxypentyl and the like; alkoxyrefers to the corresponding alkyl ethers thereof.

In the use of the term hydroxyalkoxy, it is understood that the hydroxygroup can occur at any available position of alkoxy other than the C-1(geminal) position. Thus hydroxyalkoxy includes, for example,2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropoxy, 5-hydroxypentoxyand the like.

Alkylene refers to a linear or branched divalent hydrocarbon radical offrom 1 to about 5 carbon atoms such as methylene, 1,2-ethylene,1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,4-(2-methyl)butylene andthe like. Alkylene can also have alkenyl or alkynyl linkages therein.

Halogen refers to the common halogens fluorine, chlorine, bromine andiodine.

As used herein, the term haloalkyl refers to a halo substituted alkyl,such as fluoroalkyl, chlorofluoroalkyl, bromochloroalkyl,bromofluoroalkyl, bromoalkyl, iodoalkyl, chloroalkyl and the like wherethe haloalkyl has one or more than one of the same or different halogenssubstituted for a hydrogen. Examples of haloalkyl includechlorodifluoromethyl, 1-chloroethyl, 2,2,2 trichloroethyl, 1,1dichloroethyl, 2-chloro, 1,1,1,2 tetrafluoroethyl, bromoethyl and thelike.

As used herein the term fluoroalkyl is a prefered subclass of haloalkyl,and refers to fluorinated and perfluorinated alkyl, for examplefluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 1,1,2,3-tetrafluorobutyl and the like.

The compounds of Formula I wherein R₃ is a basic nitrogen containingheterocycle are sufficiently basic to form acid addition salts and areuseful both in the free base form and the form of acid-addition salts,and both forms are within the purview of the invention. Theacid-addition salts are, in some cases, a more convenient form for use,and in practice the use of the salt form inherently amounts to the useof the base form. The acids which can be used to prepare theacid-addition salts include preferably those which produce, whencombined with the free base, medicinally acceptable salts, that is,salts whose anions are relatively innocuous to the animal organism inmedicinal doses of the salts so that the beneficial properties inherentin the free base are not vitiated by side effects ascribable to theanions. Examples of appropriate acid-addition salts include thehydrochloride, hydrobromide, sulfate, acid sulfate, maleate, citrate,tartrate, methanesulfonate, p-toluenesulfonate, dodecyl sulfate,cyclohexanesulfamate, and the like. However, other appropriatemedicinally acceptable salts within the scope of the invention are thosederived from other mineral acids and organic acids. The acid-additionsalts of the basic compounds can be prepared by dissolving the free basein aqueous alcohol solution containing the appropriate acid andisolating the salt by evaporating the solution, or by reacting the freebase and an acid in an organic solvent, in which case the salt separatesdirectly, is precipitated with a second organic solvent, or byconcentration of the solution or by any one of several other knownmethods. Although medicinally acceptable salts of the basic compoundsare preferred, all acid-addition salts are within the scope of thepresent invention. All acid-addition salts are useful as sources of thefree base form even if the particular salt per se is desired only as anintermediate product, as, for example, when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a medicinally acceptable salt by ion exchangeprocedures.

Alternatively, the N-oxide of those compounds having nitrogenheterocycles can be prepared by exposing the compound of the inventionto a peroxide such as m-chloroperbenzoic acid and the like. TheseN-oxides have similar activity to their free base analogs.

The structures of the compounds of the invention were established by themode of synthesis, by elemental analysis, and by infrared, ultraviolet,nuclear magnetic resonance and mass spectroscopy. The course of thereactions and the identity and homogeneity of the products were assessedby thin layer chromatography (TLC) or gas-liquid chromatography (GLC) orother art recognized means of monitoring organic reactions.

As described herein a noninteracting solvent can be N-methyl pyrrolidine(NMP), methylene chloride (CH₂ Cl₂), tetrahydrofuran (THF), benzene orany other solvent that will not take part in the reaction. In apreferred method, the preparation of compounds of the invention is donein dried solvents under an inert atmosphere. Certain reagents used inexample preparations are specified by abbreviation: triphenylphosphine(TPP), lithium aluminum hydride (LAH), triethylamine (TEA),diisopropylethylamine (DIPEA), and diethyl azodicarboxylate (DEAD).Ether is diethyl ether unless otherwise specified.

Compounds of Formula I can be prepared by several methods:

Compounds of Formula I can be prepared by the reaction of theappropriate hydroxy-Y-(Azo) and the appropriate 4-substituted phenol bythe reaction described in U.S. Pat. No. 5,242,924, incorporated hereinby reference.

Compounds of Formula I can be prepared by reaction of the appropriatephenol and the appropriate halo-Y-(Azo) as described in U.S. Pat. No.4,942,241, incorporated herein by reference.

Compounds of formula I can be prepared by reaction of the appropriatephenol with a suitably X-Y-halide or X-Y-OH compound wherein X is afunctional group which can be elaborated into or substituted by aheterocycle of (Azo) type by the methods described above. The azole orazine moiety is then elaborated in a final step in the synthesis. Thismethod is preferred were the azole or azine (Azo) is triazine,thiazolyl, oxadiazolyl and the like.

Alternatively, a suitably functionalized azole or azine moiety issubstituted onto the X-Y-O R₁ -R₂ -R₃ -phenyl! compound in the finalstep. For example, a preferred method of preparation of molecules whereAzo is imidazole comprises the formation of a halo-Y-O-R1-R2-R3-phenylcompound and reacting it with imidazole to form a 1-imidazolyl compoundof formula I. Alternatively a functionalized imidazole, such as atin-imidazole derivative can be reacted with Y-O-R₁ -R₂ -R₃ -phenylcompound wherein Y contains terminal unsaturation, yielding, forexample, the 5 imidazolyl compound of formula I. These coupling methodsare preferred when Azo is imidazolyl, pyrazolyl and the like.

Where R₃ is phenyl or heterocyclyl, compounds of formula I can also beprepared by reacting the hydroxy-Y-(Azo) or halo-Y-(Azo) moiety with anappropriate 4-functionalized-R₁ -R₂ -phenol, using the methods describedabove. The resulting Azo-Y- 4-functionalized R₁ -R₂ -phenyl! compound isthen reacted with a functionalized heterocycle or phenyl ring to providea compound where R₃ is phenyl or heterocyclyl. For example, a 4-boratesubstituted phenoxy compound is reacted with a halopyridine, for example4-bromopyridine, to give a compound of formula I wherein R₃ is4-pyridyl. Alternatively, the 4-functionalized group on the phenoxy ringcan be chosen so that it can be elaborated into a heterocycle in thefinal steps of the synthesis. This method is preferred with R₃heterocycles having 2 or more heteroatoms, such as 5-halo alkyl-1,2,4oxadiazolyl and the like.

For example, the compound of Formula I can be prepared from anappropriate 4-substituted R₁, R₂ phenoxy-Y-(Azo) species, wherein the4-phenoxy position is functionalized with the desired heterocycleprecursor. For example, 4- Azo)-Y-O-R₁ -R₂ -!benzaldehydes, and 4-(Azo)-Y-O-R₁ -R₂₋ !benzonitriles are prepared from known materials usingmethods well known in the art. It will be understood that whenω-(Azo)-Y- is replaced by a suitable protecting group, this method willproduce protected phenol, which is then deprotected to yield a phenol.This phenol is then useful in preparing the compound of formula I whenreacted with the appropriate ω-(Azo)alkanol or ω-(Azo)alkylhalide.! Theheterocycle on the phenoxy ring may be elaborated in a final step whenpreparing a compound of formula I. Suitable functionality in the4-phenoxy position will depend upon the heterocycle sought in the finalproduct. For example, where Het is 1,2,4-oxadiazolyl ##STR3## compoundsare prepared from the appropriate 4- Z-O-R₁ -R₂ -!benzonitrile, where zis Y-(Azo) if the target compound is a compound of formula I, byreaction with hydroxylamine hydrochloride in a noninteracting solvent,preferably pyridine or an alkanol, for example, methanol, ethanol,n-butanol, and the like, in the presence of a base, such as potassiumcarbonate, at a temperature between ambient temperature and the boilingpoint of the solvent. The product thus obtained is then reacted with anacid anhydride of formula (R'CO)₂ O, (where R' is alkyl, haloalkyl);with R' appearing as a substituent on R₃ of the product. For exampletrifluoroacetic anyhdride, or acetic anhydride, yield trifluormethyl ormethyl as R' respectively. The product is a compound of formula I wherethe starting material is the 4-cyano R₁ -R₂ -phenoxy-4-(Azo).Alternatively, if Z, is a protecting group a 4- ZO-R₁ -R₂₋!phenyl(R')oxadiazole is prepared from the 4-ZO-R₁ -R₂ -benzonitrile,which is then deprotected and used in one of the methods describedabove.

Where the compound of formula I has the same heterocyle at both ends ofthe molecule, these heterocycles can also be elaborated at the same timefrom a suitable precursor by adding the appropriate excess of reactants,and using the standard reaction conditions.

It will be appreciated that neither the timing of the elaboration of theheterocyclic substituents nor the order of assembly of the intermediateis crucial to the successful synthesis of compounds of Formula I. Thusby judicious choice of reactants one can prepare any of the compounds ofFormula I, by several different routes.

However, the skilled artisan will immediately recognize that thesynthesis may be more successful when performing steps in a certainorder so as to avoid side products. For example, the skilled artisanwill appreciate that certain of the heterocycles disclosed herein aresusceptible to nucleophilic attack. This susceptibility may causeundesired side products caused by elaborating the (Azo) heterocycle orthe R₃ heterocycle before the coupling of the phenoxy an alkyl halide oralkanol moiety. The susceptibility to nucleophiles is also aconsideration when determining which heterocycle is to be elaborated,for example if the phenoxyalkyl moiety has been formed, but lacks Azoand R₃ heterocycles. For example, a prefered method of preparingcompounds of formula I wherein R₃ is trifluoromethyl oxadiazolyl, is toform the (Azo) -Y-O-(R₁ -R₂) benzonitrile and elaborate the oxadiazolylmoiety last, to avoid any undesired side reactions. As a furtherexample, triazines as R₃ or (Azo) (and other π deficient rings) areelaborated after formation of the phenoxyalkyl moiety. Theseconsiderations are spelled out in detail in Katritzky and ReesComprehensive Heterocyclic Chemistry (1984).

When preparing compounds of formula I it is advantageous to arrange theorder of synthesis so that yields are maximized, thus elaboration ofheterocycles which are nucleophile-susceptible may be delayed until latein the synthesis. In such cases it may be advantageous to prepare afunctionalized precursor in the position of the heterocycle such asester, amide, cyano group and the like; then elaborate the heterocycletherefrom. For example a preferred method of preparing a compoundwherein Azo is 2-alkyl tetrazolyl is to prepare the correspondingcyanoalkoxyphenyl heterocycle or cyano alkoxy phenyl heterocycleprecursor. Other processes will be understood by analogy.

The phenols used to prepare compounds of Formula I are generally knownin the art or they can be prepared by known methods. Their preparationis described in U.S. Pat. Nos. 4,942,241; 4,945,164; 5,051,437;5,002,960; 5,110,821; 4,939,267; 4,861,971; 4,857,539; 5,242,924; or4,843,087 incorporated herein by reference. Any phenol disclosed inthese patents, or known in the art, can be reacted with ahydroxy-Y-(Azo) or halo-Y-(Azo) moiety to prepare compounds of formulaI. Of course, other known phenols can be used to prepare compounds offormula I. Examples include any 4-phenylphenols, or4-alkoxycarbonylphenols, substituted or unsubstituted as describedabove, all of which are well known and useful.

In addition, R₃ -phenols (R₃ =heterocycle) can be prepared from thesuitably protected phenols which have been functionalized at the 4position by a group such as cyanide, aldehyde, halide, acid chloridegroup or the like, as described above or in U.S. Pat. Nos. 4,942,241;4,945,164; 5,051,437; 5,002,960; 5,110,821; 4,939,267; 4,861,971;4,857,539; 5,242,924; or 4,843,087 each incorporated herein byreference, to obtain the the corresponding 4-heterocyclyl phenol bymeans well known in the art.

Hydroxy-Y-(Azo) or halo-Y-(Azo) compounds are prepared from known(Azo)halides, (Azo)-alcohols, (Azo)-acids or (Azo)-carboxyalkylcompounds or from any other known (Azo) species that can be suitablyfunctionalized by known methods. For a review of reaction methods, seeKatritsky and Rees, Comprehensive Heterocyclic Chemistry Volume 2,especially sections 2.12-2.14 (Pergamon, 1984). This reaction method isanalogous to the method described for preparing compounds of formula Ifrom X functionalized-Y-O-R₁ -R₂ -R₃ -phenyl compounds.

For example, thiazole triflate, can be reacted with a terminallyunsaturated tin species of formula X-Y-Z where Y has unsaturation whereX═SnR_(n), and where Z is a different functional group, not taking partin this reaction. For example, tributyltin alkynyl species, terminallyunsaturated esters, acids or alcohols; such as alkynyl alkanols, α,βunsaturated esters and the like, are all useful as intermediates. Theresulting unsaturated alkanols, esters and acids may be partially orcompletely reduced by known methods. Such reduction methods include, butare not limited to; palladium or carbon, lithium aluminum hydride andthe like to give the corresponding alkanol. Alternatively, such alkanolsmay be prepared by reaction of (Azo) ketones, aldehydes and the likewith phosphonates and the like, for example under Wittig conditions, toyield the corresponding unsaturated species which can be reduced asdescribed above.

Simple chemical transformations which are conventional and well known tothose skilled in the art of chemistry can be used for effecting changesin functional groups in the compounds of the invention. For example,acylation of hydroxy- or amino-substituted species to prepare thecorresponding esters or amides, respectively; alkylation of phenyl orother aromatic and heterocyclic substituents; cleavage of alkyl orbenzyl ethers to produce the corresponding alcohols or phenols; andhydrolysis of esters or amides to produce the corresponding acids,alcohols or amines, preparation of anhydrides, acid halides, aldehydes,simple aromatic alkylation and the like as desired can be carried out.

Moreover, it will be appreciated that obtaining the desired product bysome reactions will be better facilitated by blocking or renderingcertain functional groups non reactive. This practice is well recognizedin the art, see for example, Theodora Greene, Protective Groups inOrganic Synthesis (1991). Thus when reaction conditions are such thatthey can cause undesired reactions with other parts of the molecule, theskilled artisan will appreciate the need to protect these reactiveregions of the molecule and act accordingly.

Starting materials used to prepare the compounds of Formula I arecommercially available, known in the art, or prepared by known methods.Many of the preparations of starting materials herein are incorporatedby reference from the patent literature.

Exemplary Disclosure

For the purpose of naming substituents in Formula I, the phenyl ring ofany compound of formula I or intermediate used in its preparation shallbe numbered; ##STR4##

Thus when a compound of formula I has substitution on the phenyl ring,it is referred to by this numbering system regardless of how thecompound is actually named. For example, if a compound is prepared andthe designation is R₁, R₂ =3,5-dimethyl, this means ##STR5## regardlessof whether 3,5-dimethyl or 2,6-dimethyl appears the name of thecompound.

For our purposes the same designations given for compounds of formula Iare used for the intermediates. Thus a phenol intermediate may have R₁,R₂ and R₃ designated after the name of the product, and thesedesignations have the same meanings as for the compound of formula I.

Preparation of Intermediates Intermediate A 1-Amino-1-hydroxyiminoethane

A solution of 3.1 g of sodium in 60 ml of methanol (dissolved undernitrogen) was added dropwise to a stirred suspension of hydroxylaminehydrochloride (9.12 g) in 20 ml of methanol over a 15 min period. Thereaction mixture was stirred at room temperature for 1.5 h, filtered,and the residual solids washed with 10 ml of methanol. To the combinedfiltrate was added 5.46 ml of acetonitrile, the resulting mixture wasallowled to reflux for 24 h, and the solid precipitate was filtered. Thefiltrate was concentrated in vacuo to yield 4.61 g (46.1%) of1-amino-1-hydroxyiminoethane as a white crystalline solid, m.p.119°-122° C.

Intermediate B 3- (3-Methyl-1,2,4-oxadiazol)-5-yl!propanol

To a mixture of 1-amino-1-hydroxyiminoethane (3 g, 40.5 mmol) andpotassium carbonate (milled; 5.6 g) under nitrogen was addedgamma-butyrolactone (3.17 g, 36.8 mmol) and the mixture was slowlyheated to 125°-130° C. for 50 min. The above mixture was heated at 125°C. for 3.5 h while adding additional gamma-butyrolactone (2×320 mg ).The above mixture was cooled, diluted with 20 ml of chloroform withstirring, and the organic layer was decanted. To the above organic layerwas added 5 g of magnesium sulfate and 10 ml of chloroform, the mixturewas stirred, and the organic layer was decanted. The solids were washedwith chloroform (3×10 ml), the combined organic layer was dried overmagnesium sulfate, and concentrated in vacuo to yield 2.82 g of a clearoil. The clear oil was purified by passing through a silica gel pad(4.5×5 cm) with ethyl acetate to afford 2.41 g (46.1%) of 3-(3-methyl-1,2,4-oxadiazol)-5-yl!propanol.

Intermediate C

1 (1,3-Dimethyl-2-phenylmethoxy-5-trimethylstannyl)-benzene.

To a solution of (1,3-dimethyl-2-phenylmethoxy)benzyl bromide (1.0 g;3.4 mmol) in 15 ml of ether at -20° C. was added under nitrogen and withstirring 1.36 ml (3.4mmol) of n-butyllithium (nBul:) and the mixture wasallowed to warm to room temperature over a period of 30 min. To theabove mixture cooled to -20° C. was added dropwise trimethyltin chloride(1.36 ml, 3.4 mmol) over a period of 3 min, and the mixture was allowedto warm to room temperature. To the resulting mixture was addedsaturated aqueous ammonium chloride solution, water, and ether. Theorganic layer was washed with brine, dried over magnesium sulfate,filtered, and the filtrate was concentrated in vacuo to yield a clearoil. The clear oil was purified through a reverse phase column (ether,95% methanol) to afford 0.68 g (53.3%) of(1,3-dimethyl-2-phenylmethoxy-5-trimethylstannyl)benzene.

2 (1,3-Dimethyl-2-phenylmethoxy-5-fluoro) benzene

A mixture of 0.83 g (1.94 mmol) of(1,3-dimethyl-2-phenylmethoxy-5-trimethylstannyl)benzene, 0.22 ml (1.94mmol) of (1-fluoro-4-iodo)benzene, and 42 mg (0.06 mmol) of PdCl₂ ((C₆H₅)₃ P)₂ in 8 ml of DMF was heated at 90° C. with stirring overnight.The mixture was cooled to room temperature, diluted with ether, andfiltered through a plug of Supercel. The organic layer was washed withwater (50 ml), brine (50 ml), dried over magnesium sulfate, andconcentrated in vacuo to yield a purple/brown solid. The solid dissolvedin methylene chloride/hexane was purified by passing it through a dryflash column eluting with hexane (500 ml), 5% ethyl acetate in hexane(200 ml), 10% ethylacetate in hexane (200 ml), 20% ethyl acetate inhexane (300 ml), and hexane. The solid product was recrystallized fromethyl acetate to afford 224 mg (41%) of(1,3-dimethyl-2-phenylmethoxy-5-fluoro)benzene.

3 2,6-Dimethyl-4(4-fluoro)phenyl!phenol

To a mixture of 350 mg of 10% Pd/C, 1 ml of water, 10 ml of methanol,and 224 mg (0.73 mmol) of (1,3-dimethyl-2-phenylmethoxy-5-fluoro)benzenewas added 230 mg (3.65 mmol) of ammonium bicarbonate and the resultingreaction mixture was allowed to react at 60° C. for 15 min. The mixturewas cooled, and diluted with ethyl acetate and water. The organic layerwas washed with water and brine, dried over magnesium sulfate, andconcentrated in vacuo to afford 150 mg (95%) of2,6-dimethyl-4(4-fluoro)phenyl!phenol.

Preparation of Example compounds of Formula I ##STR6##

EXAMPLE 1

1A 5-4-(3-Cyano)propyloxy-3,5-dimethyl!phenyl-2-methyltetrazole(AZO-Y-=3-cyanopropyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

To a stirred solution of 5-4-hydroxy-3,5-dimethyl!phenyl-2-methyltetrazole (15.52 g; 73.7 mmol) and4-bromobutyronitrile (12 g; 81.1 mmol) in 200 ml of DMF under nitrogenwas added 20.38 g (0.147 mol) of potassium carbonate and the resultingmixture was heated at 80° C. for 2 h. The above reaction mixture wascooled, diluted with 300 ml of water, and extracted with ether (3×300ml). The organic layer was washed with water (4×100 ml), 10% NaOHsolution, water (1×200 ml), and dried over magnesium sulfate. Theorganic layer was concentrated in vacuo, the residue was dissloved in 50ml of methylene chloride and concentrated in vacuo to afford 19.3 g(86.8%) of 5-4-(3-cyano)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole. The productwas purified by LC column chromatography (900 g Keiselgel; 30% ethylacetate in hexane) to afford 13.16 g of 5-4-(3-cyano)propyloxy-3,5-dimethyl!phenyl-2-methyltetrazole as whitecrystalline solids.

1B 5- 4-3-(Tetrazol-5-yl)propyloxy!-3,5-dimethyl!phenyl-2-methyltetrazole(AZO-Y-=3-(tetrazol-5-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A solution of 7 g (26 mmol) of 5-4-(3-cyano)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole, 5.03 g(77.4 mmol) of sodium azide, 5.37 g (39 mmol) of triethylaminehydrochloride in 75 ml of N-methyl-2-pyrrolidinone under nitrogen washeated at 150° C. with stirring overnight. To the mixture was added 22.2g of sodium nitrite in 222 ml of deionized water and the resultingmixture was acidified carefully with 20% sulfuric acid solution to pH 4.The solid product was filtered, washed thoroughly with deionized water,and dried in vacuo. The mother liquor was refiltered and the combinedsolids dried in vacuo to afford 8.86 g (96%) of 5- 4-3-(tetrazol-1-yl)propyloxy!-3,5-dimethyl!phenyl-2-methyl-tetrazole, as alight tan solid product, m.p. 175°-176° C.

1C 5-4-(2-Methyltetrazol-5-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=3-(2-methyltetrazol-1-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

To a solution of 7.3 g (23.2 mmol) of 5-4-(3-tetrazol-5-yl)propyloxy-3,5-dimethyl!phenyl-2-methyltetrazole in100 ml of N-methylpyrrolidone (NMP) under nitrogen with stirring wasadded 10.12 ml (58.1 mmol) of diisopropyl-ethylamine. To the resultingmixture was added dropwise 1.81 ml (29 mmol) of iodomethane in 25 ml ofNMP over a period of 15 min (the temperature rose to 29° C. during theaddition) and the mixture was stirred at room temperature overnight. Themixture was diluted with 600 ml of water/NMP (5:1), extracted with ethylacetate, and the organic layer was dried over magnesium sulfate andfiltered through a plug of silica. The organic layer was concentrated invacuo to yield 11.07 g of a crude product which was purified by flashcolumn chromatography (300 g of Keiselfel; ethyl acetate/hexane, 1:1)and recrystallization from methanol to afford 2.99 g of 5-4-(2-methyltetrazol-1-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole,as a white crystalline solid, m.p. 112°-113° C., and 2.19 g of 5-4-(l-methyltetrazol-5-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole,as a white crystalline solid, m.p. 135°-136° C.

EXAMPLE 2

2A 4- 2,6-Dimethyl-4-(2-methyl-tetrazol-5-yl)!phenyloxy!butyricamide(AZO-Y-=1-oxo-1-aminobutyl, R₁,R₂ =2,6-dimethyl, R₃=2-methyltetrazol-5-yl)

A stirred solution of 5-4-(3-cyano)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(1 g; 3.7mmol) and mercuric acetate (1.18 g; 3.7 mmol) in 100 ml of glacialacetic acid was allowed to reflux under nitrogen for 24 h. After adding350 mg of mercuric acetate, the mixture was allowed to reflux for anadditional 48 h. The reaction mixture was cooled, poured over 150 ml ofice/water, and the mixture was extracted with methylene chloride (5×75ml). The organic layer was washed with dilute sodium bicarbonatesolution (2×200 ml), water, brine, and dried over magnesium sulfate. Theorganic solution was concentrated in vacuo to afford 1.08 g (theory) of4- 2,6-dimethyl-4-(2-methyltetrazol-5-yl)!phenyloxy!butyric amide, as apale yellow solid.

2B 5- (3,5-Dimethyl)-4-4-oxo-4-(1-dimethylaminoethyleneamino!-butyloxy!phenyl-2-methyltetrazole(AZO-Y-=4-oxo-4-(1-dimethyl-aminoethyleneamino)-butyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 1.0 g of 4-2,6-dimethyl-4-(2-methyltetrazol-5-yl)!phenyloxy!-butyric amide and 2.0ml of N,N-dimethylacetamide dimethyl acetal under nitrogen was heatedwith stirring at 150° C. for 4 h. The excess acetal was removed in vacuoand 1.3 g of 5- (3,5-dimethyl)-4-4-oxo-4-(1-dimethyl-aminoethylene)amino!butyloxy!phenyl-2-methyltetrazolewas isolated as a red oil (a crude oil) which was used without furtherpurification.

2C 5-4-(3-Methyl-1,2,4-oxadiazol-5-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=3-methyl-1,2,4-oxadiazol-5-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

To a solution of sodium hydroxide (176 mg), 0.89 ml of distilled water,310 mg (4.4 mmol) of hydroxylamine hydrochloride, and 4.2 ml ofp-dioxane in 8.5 ml of 70% of acetic acid/water placed in 50 ml of flaskequiped with a drying tube was added 1.3 g (3.6 mmol) of 5-(3,5-dimethyl)-4-4-oxo-4-(1-dimethylaminoethylene)amino!butyloxy!phenyl-2-methyltetrazoleand the mixture was heated at 90° C. for 4h. To the reaction mixture wasadded 30 ml of water and 30 ml of chloroform, and the aqueous layer wasextracted with chloroform (3×15 ml). The combined organic layer wasdried over magnesium sulfate, filtered, and passed through a silica gelpad. The organic solution was concentrated in vacuo to yield 1.0 g of acrude yellow oil which was purified by a flash column chromatography(100 g of Keisel gel; 40% ethyl acetate/hexane) followed byrecrystallization from methanol to afford 492 mg of 5-4-(3-methyl-1,2,4-oxadiazol-5-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(VOKB-86-A; WIN 62002, from fraction A-C) as a white solid, m.p.87.5-88.5° C. and 665 mg of 5-4-(3-methoxycarbonyl)propyloxy-3,5-dimethyl!phenyl-2-methyltetrazole asa white solid, m.p. 107.5°-108° C.

EXAMPLE 3

A. 3-4-(3-Methyl-1,2,4-oxadiazol-5-yl)propyloxy-3,5-dimethyl!phenyl-5-methyl-1,2,4-oxadiazole(AZO-Y-=3-methyl-1,2,4-oxadiazol-5-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =5-methyl-1,2,4-oxadiazol-3-yl)

To a mixture of 540 mg (38.07 mmol) of 3-(3-methyl-1,2,4-oxadiazol)-5-yl!propanol, 860 mg (41.87 mmol) of5-methyl-3- 4-hydroxy-3,5-dimethyl!-phenyl-1,2,4-oxadiazole, and 1.1 gof triphenylphosphine in 5 ml of THF under nitrogen, which was stirredand chilled to 0° C., was added 730 mg (1.1 eq) of diethylazodicarboxylate (DEAD) in 5 ml of THF over a period of 5 min. Thereaction mixture was stirred at room temperature for 1.5 h, diluted withwater, and extracted with ether (2×). The organic layer was washed with10% sodium hydroxide solution, water, brine, and dried over magnesiumsulfate. The organic solution was diluted with hexane (equal volume) andconcentrated in vacuo to yield 1.48 g of a white solid which waspurified by flash column chromatography (silica gel; 2.5×11 cm, 40%ethyl acetate in hexane) to afford 1.11 g (88.8%) of 3-4-(3-methyl-1,2,4-oxadiazol-5-yl)propyloxy-3,5-dimethyl!phenyl-5-methyl-1,2,4-oxadiazole,as a white solid, m.p.88°-89° C. (recrystallized from methanol and driedin vacuo).

EXAMPLE 4 3-4-(3-Methyl-1,2,4-oxadiazol-5-yl)propyloxy-3,5-dimethyl!phenyl-5-trifluoromethyl-1,2,4-oxadiazole(AZO-Y-=3-methyl-1,2,4-oxadiazol-5-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =5-trifluoro-methyl-1,2,4-oxadiazol-3-yl)

To a mixture of 460 mg (32.69 mmol) of3-(3-methyl-1,2,4-oxadiazol-5-yl)propanol, 930 mg (35.96 mmol) of5-trifluoromethyl-3- 4-hydroxy-3,5-dimethyl!phenyl-1,2,4-oxadiazole, and940 mg of tripenylphosphine in 5 ml of THF under nitrogen, which wasstirred and chilled to 0° C., was added 630 mg (1.1 eq) of diethylazodicarboxylate (DEAD) in 5 ml of THF over a period of 5 min. Thereaction mixture was stirred at room temperature for 1.5 h, diluted withwater, and extracted with ether (3×). The oraganic layer was washed with2% sodium hydroxide solution, water, brine, and dried over magnesiumsulfate. The organic solution was concentrated in vacuo to yield 2.28 gof a white solid which was purified by flash column chromatography(silica gel; 1.5×9 cm, 20% ethyl acetate in hexane) to afford 1.04 g(83.2%) of 3-4-(3-methyl-1,2,4-oxadiazol-5-yl)propyloxy-3,5-dimethyl!phenyl-5-trifluoromethyl-1,2,5-oxadiazole,as a yellow oil. The oil was crystallized from hot methanol and dried invacuo to afford 638 mg of a solid product, m.p. 79°-80° C.

EXAMPLE 5

A. 5-4-(3-Ethoxycarbonyl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=3-(ethoxycarbonyl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 5- 4-hydroxy-3,5-dimethyl!phenyl-2-methyltetrazole (10.21g; 50 mmol), ethyl 4-bromobutyrate (8 ml; 55 mmol), 6.9 g (50 mmol) ofpotassium carbonate, and 8.25 g (55 mmol) of sodium iodide in 100 ml ofacetonitrile was allowed to reflux under nitrogen for 43 h. The reactionmixture was concentrated in vacuo, the residue was stirred with 10% NaOHsolution, and the resulting mixture was filtered. The residual solid andthe filtered brown oil were triturated with methylene chloride, theorganic layer was washed with water, brine, and dried over magnesiumsulfate. The organic layer was concentrated in vacuo, the residual oilwas triturated with methanol and concentrated in vacuo. The aboveresidue was purified by passing through a plug of silica gel withmethylene chloride followed by concentration in vacuo to afford 5.38 g(34%) of 5-4-(3-ethoxycarbonyl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole, asa yellow oil.

B. 5-4-(3-Carboxy)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=3-(carboxy)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 5-4-(3-ethoxycarbonyl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(5.38 g; 17 mmol), lithium hydroxide (0.46 g; 19 mmol) in 50 ml ofmethanol and 5 ml of water with stirring and under nitrogen was allowedto reflux for 30 min. The mixture was cooled to room temperature,concentrated in vacuo, the residue was treated with water, and theresulting mixture was extracted with ether. The aqueous layer wasacidified with conc. HCl solution with stirring, filtered, and the solidproduct (5.02 g ) was dried in vacuo and recrystallized from propylacetate to afford 3.75 g (76%) of 5-4-(3-carboxy)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole, as awhite solid, m.p. 120°-121° C.

C. 5-4-(3-Propargylaminocarbonyl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=3-(propargylamino-carbonyl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 5-4-(3-carboxy)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole (2.94 g;10 mmol) and carbonyl diimidazole (1.95 g; 12 mmol) in 50 ml ofmethylene chloride under nitrogen was refluxed with stirring for 15 min.The mixture was cooled, 1 ml (15 mmol) of propargylamine was added inone portion, and the resulting reaction mixture was stirred for 1 h atroom temperature. The reaction mixture was quenched with 3N HCl solutionwith stirring, the organic layer was washed with water, brine, and driedover magnesium sulfate. The organic solution was concentrated in vacuoand the residual solid (3.38 g; m.p. 126°-128° C.) was recrystallizedfrom methanol to afford 2.47 g (74%) of 5-4-(3-propargylaminocarbonyl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazoleas a white crystalline solid, m.p. 129°-130° C.

D. 5-4-(5-Methyl-oxazol-2-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=5-methyloxazol-2-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 5-4-(3-propargylaminocarbonyl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(980 mg; 3 mmol) and mercuric acetate (50 mg; 0.16 mmol) in 10 ml ofglacial acetic acid was allowed to reflux for 5 h with stirring andunder nitrogen and then cooled to room temperature. The mixture wasconcentrated in vacuo, the residue was dissolved in methylene chloride,and the organic layer was washed with 10% potassium carbonate, water,brine, and dried over magnesium sulfate. The organic layer wasconcentrated in vacuo and the residual yellow oil (880 mg) was passedthrough a silica gel plug (with ether) to yield 660 mg of a white oilwhich was purified by MPLC chromatography (silica gel, hexane/ethylacetate, 1:1) to afford 530 mg (54%) of 5-4-(5-methyl-oxazol-2-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazoleas a colorless oil. The oil was crystallized from methanol andrecrystallized from acetonitrile to yield white crystalline solids, m.p.80°-81° C.

EXAMPLE 6

A. 5-(4-(3-Ethoxycarbonyl)propyloxy-3,5-dimethyl!phenyl)-2-methyl-tetrazole(AZO-Y-=3-(ethoxycarbonyl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 5-( 4-hydroxy-3,5-dimethyl!phenyl)-2-methyltetrazole (10.21g; 50 mmol), ethyl 4-bromobutyrate (10 ml; 70 mmol), 13.8 g (100 mmol)of potassium carbonate, and 11.6 g (70 mmol) of sodium iodide in 200 mlof acetonitrile was allowed to reflux under nitrogen for 17 h. Thereaction mixture was concentrated in vacuo, the residue was stirred withethyl acetate, filtered, and the filtrate was washed with 10% NaOHsolution, water, and brine. The organic layer was dried over magnesiumsulfate, filtered, and concentrated in vacuo to afford 17.49 g of 5-4-(3-ethoxycarbonyl)propyloxy-3,5-dimethyl!phenyl-2-methyltetrazole, asa brown oil.

B. 5-4-(3-Carboxy)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=3-(carboxy)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 5-4-(3-ethoxycarbonyl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(15.9 g; 50 mmol), lithium hydroxide (1.2 g; 50 mmol) in 100 ml ofmethanol and 10 ml of water with stirring and under nitrogen was allowedto reflux for 1 h. After adding an additional lithium hydroxide (5equiv), the mixture was refluxed for additional 4 h, cooled to roomtemperature, and concentrated in vacuo. The residue was treated withwater and charcoal, and the resulting mixture was filtered. The aqueouslayer was acidified with conc. HCl solution with stirring, filtered, andthe solid product (12.27 g; 91%) was dried in vacuo to afford 5-4-(3-carboxy)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole, as whitesolids, m.p. 118°-119.5° C.

C. 4- 4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenyloxy!butanoylchloride(AZO-Y-=3-(chlorocarbonyl)propyl, R₁,R₂ =3,5-dimethyl, R₃=2-methyltetrazol-5-yl)

A mixture of 5-4-(3-carboxy)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole (5.81 g;20 mmol), 20 ml of thionyl chloride, and 4 drops of DMF was stirred atroom temperature under nitrogen for 48 h. The mixture was concentratedin vacuo to afford 6.88 g of 4-4-(2-methyltetrazol-5-yl)-2,6-dimethylphenyloxy!butanoyl chloride, as atan solid.

D. 5-4-(4-Oxo-4-diazomethyl)butyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=4-oxo-4-diazomethylbutyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A solution of Diazald (11.93 g;56mmol) dissolved in 110 ml of ether wasfiltered into a dropping funnel. This solution was added dropwise(approx 4 drops/min) to a stirred solution of KOH (2.8 g) in 20 ml ofethanol/water (3:1) warmed at 65° C. To the resulting mixture was addeda solution of 4-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenyloxy!butanoyl chloride (20mmol) in ethanol/methylene choride at 0° C. with stirring over a periodof 35 min. Ether (25 ml) was added dropwise through a dropping funnel at0° C. and the mixture was allowed to warm to room temperature gradually.After bubbling nitrogen through, the mixture was concentrated in vacuoto yield 6.84 g of a yellow solid. The solid was purified by silica gelcolumn chromatography (hexane/ethyl acetate, 1:1) to afford 3.83 g(60.8%) of 5-4-(4-oxo-4-diazomethyl)butyloxy-3,5-dimethyl!phenyl-2-methyltetrazole,as a yellow solid.

E. 5-4-(2-Methyl-oxazol-5-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=2-methyloxazol-5-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =3-methyltetrazol-1-yl)

A solution of 1-4-(4-oxo-4-diazomethyl)butyloxy-3,5-dimethyl!phenyl-3-methyl-tetrazole(1.4 g; 4.45 mmol) in 20 ml of acetonitrile was added dropwise to borontrifluorideetherate in 40 ml of acetonitrile under nitrogen withstirring in an ice-bath over a period of 35 min. The mixture was warmedto room temperature, stirred overnight, and then poured into 10% NaOHsolution. To the above mixture was added ether, and the organic layerwas washed with water, brine, and dried over magnesium sulfate. Theorganic layer was concentrated in vacuo and the residual yellow oil(1.36 g) was purified by passing through a silica gel column with ethylacetate to afford 0.72 g (49%) of 5-4-(2-methyl-oxazol-5-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole,as a white solid, m.p. 67°-68° C. (recrystallization fromtriethylamine).

EXAMPLE 7

A. 4-4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenyloxy!butanamide(AZO-Y-=4-oxo-4-amino)butyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 5-4-(3-Carboxy)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole (2.9 g; 10mmol) and carbonyl diimidazole (1.95 g; 12 mmol) in 50 ml of THF undernitrogen was allowed to reflux for 5 h with stirring. The mixture wascooled to room temperature, chilled in an ice-bath, and 5 ml of 30%ammonium hydroxide was added in one portion, and the resulting mixturewas allowed to react with stirring at room temperature overnight. Themixture was concentrated in vacuo, the residue was triturated in waterand filtered to afford 2.72 g (94%) of 4-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenyloxy!-butanamide, as a whitesolid, m.p.155°-156° C.

B. 5-4-(4-Chloromethyl-oxazol-2-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=4-chloromethyl-oxazol-2-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 4-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenyloxy!-butanamide (530 mg;1.83 mmol) and 1,3-dichloroacetone (600 mg; 4.73 mmol) in 25 ml oftoluene was allowed to reflux with stirring under nitrogen for 16 h. Thereaction mixture was filtered through a plug of silica gel eluting withhexane/ethyl acetate (6:4) and 370 mg of a yellow oil was obtained. Theoil was purified by chromatography (HPLC; hexane/ethyl acetate, from 7:3to 6:4) to afford 304 mg (14%) of 5-4-(4-chloromethyl-oxazol-2-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole,as an oil.

C. 5-4-(4-Chloromethyl-oxazol-2-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=4-chloromethyl-oxazol-2-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 4-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenyloxy!-butanamide (1.75 g;6.05 mmol) and 1,3-dichloroacetone (1.26 g; 9.9 mmol) in 50 ml oftoluene, placed in a flask equipped with a Dean-Stark trap, was allowedto reflux with stirring under nitrogen for 16 h. After adding additional1,3-dichloroacetone (530 mg; 4.2 mmol), the mixture was allowed toreflux overnight. The reaction mixture was cooled and concentrated invacuo and the residue was purified by chromatography (HPLC; hexane/ethylacetate,6:4; ethyl acetate, and 10% propanol in ethyl acetate) to afford5-4-(4-chloromethyl-oxazol-2-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(1.53 g; theory), as an oil.

D. 5-4-(4-Methyl-oxazol-2-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=4-methyloxazol-2-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 5-4-(4-chloromethyl-oxazol-2-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(160 mg; 0.44 mmol) and lithium aluminum hydride (5 equiv) in 15 ml ofTHF was allowed to reflux under nitrogen with stirring for 15 min,cooled, and quenched with saturated ammonium chloride solution. Theabove mixture was filtered through supercel and purified bychromatography (silica gel; methylene chloride/ethyl acetate, 1:1) toafford 76 mg (32%) of 5-4-(4-methyl-oxazol-2-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazoleas a white crystalline solid, m.p. 110°-112° C.

EXAMPLE 8

A. 5-4-(3-Bromo)propyloxy-3,5-dimethyl!phenyl-2-methyltetrazole(AZO-Y-=3-bromopropyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

To a mixture of 2.78 g (20 mmol) of 3-bromopropanol, 4.9 g (24 mmol) of5- 4-hydroxy-3,5-dimethyl!phenyl-2-methyltetrazole, and 3.78 ml (24mmol) of diethyl azodicarboxylate (DEAD) in 50 ml of THF(dry) was addeddropwise at 0° C. 6.29 g (24 mmol) of tripenylphosphine in 100 ml ofTHF(dry) under nitrogen over a period of 1 h. The mixture waspartitioned between 500 ml of water and 100 ml of ether. The aqueouslayer was extracted with 100 ml of ether, the combined organic layer waswashed with 10% sodium hydroxide solution, brine, and dried overmagnesium sulfate. The organic solution was concentrated in vacuo toyield 13.8 g of a brown oil which was purified by flash columnchromatography (Keiselgel 60; 50×460 mm, 20% ethyl acetate in hexane) toafford 5.38 g (82%) of 5-4-(3-bromo)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole, as a whitesolid.

B. 5- 4-3-(Imidazol-1-yl)propyloxy!-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=-(3-imidazol-1-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 2.6 g (8 mmol) of 5-4-(3-bromo)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole, 1.09 g (10mmol) of imidazole, 2.76 g (20 mmol) of potassium carbonate, and 130 mg(0.8 mmol) of potassium iodide in 35 ml of N-methyl-2-pyrrolidinoneunder nitrogen was allowed to react at 60°-70° C. with stirring for 4 h.The reaction mixture was cooled and 200 ml of water, 100 ml of brine,and 75 ml of ether were added. The aqueous layer was extracted withether (3×50 ml) and the combined organic layer was washed with water andbrine. The organic layer was extracted with 1N HCl solution (3×50 ml)and the acidic solution was basified with 1N NaOH solution (to pH=8).The above mixture was extracted with methylene chloride (3×30 ml), theorganic layer dried over magnesium sulfate, and concentrated in vacuo toyield 2.09 g of a yellow oil. The oil which was purified by flash columnchromatography (2×; 120 g Keisel gel 60; 10% isopropanol in chloroform,5% isopropanol in chloroform ) to afford 1.57 g of 5- 4-3-(imidazol-1-yl)propyloxy!-3,5-dimethyl!phenyl-2-methyltetrazole as awhite crystalline solid, m.p. 92.5°-94° C. (from ether).

C. 5- 4-3-(2-Methyl)imidazol-1-yl!propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=3-(2-methylimidazol-1-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 2.94 g (9 mmol) of 5-4-(3-bromo)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole, 1.72 g (20mmol) of 2-methylimidazole, 3.63 g (21 mmol) of potassium carbonate, and170 mg (1 mmol) of potassium iodide in 35 ml of N-methyl-2-pyrrolidinoneunder nitrogen was allowed to react at 60°-70° C. with stirringovernight. The reaction mixture was cooled and 200 ml of water, 100 mlof brine, and 75 ml of ether were added. The aqueous layer was extractedwith ether (3×50 ml) and the combined organic layer was washed withwater and brine. The organic layer was extracted with 1N HCl solution(3×50 ml) and the acidic solution was basified with 1N NaOH solution (topH=8). The above mixture was extracted with methylene chloride (3×30ml), the organic layer dried over magnesium sulfate, and concentrated invacuo to yield 2.67 g of a solid. The solid product was purified byflash column chromatography (2×; 120 g Keisel gel 60; 2.5% isopropanolin chloroform) to afford 1.77 g of 5- 4-3-(2-methyl)imidazol-1-yl!propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazoleas a white crystalline solid, m.p. 121°-122.5° C. (from ether).

D. 5- 4-3-(4-Methyl)imidazol-1-yl!propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=3-(4-methylimidazol-1-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A mixture of 3.6 g (11 mmol) of 5-4-(3-bromo)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole, 1.09 g (10mmol) of 4-methylimidazole, 3.87 g (28 mmol) of potassium carbonate, and190 mg (11 mmol) of potassium iodide in 35 ml ofN-methyl-2-pyrrolidinone under nitrogen was allowed to react at 60°-70°C. with stirring overnight. The reaction mixture was cooled and 200 mlof water, 100 ml of brine, and 50 ml of ether were added. The aqueouslayer was extracted with ether (3×50 ml) and the combined organic layerwas washed with water/brine(2×50 ml;1:1). The organic layer wasextracted with 1N HCl solution (3×50 ml) and the acidic solution wasbasified with 1N NaOH solution (to pH=8.5) The above mixture wasextracted with methylene chloride (3×30 ml), the organic layer driedover magnesium sulfate, and concentrated in vacuo to yield 2.92 g 67.3%of a yellow oil. The oil was purified by flash column chromatography(580 g Keiselgel 60; 1% isopropanol in chloroform). The combinedfractions (fr 213-432) was concentrated in vacuo to yield 2.43 g of ayellow oil which was purified by successive fractional crystallizationsfrom ether/methylene chloride to afford 340 mg of 5- 4-3-(4-methyl)imidazol-1-yl!propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazoleas a pale yellow crystalline solid, m.p. 126°-127° C.

EXAMPLE 9

A. 2- 4-4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-1-hydroxy-butyl!-1-methylimidazole

To a cold solution of 1-methylimidazole (164 mg, 2 mmol) in 20 ml of THFwas added at -30° C. n-BuLi (2.5M in hexane, 0.8 ml, 2 mmol). Themixture was stirred at -30°-40° C. for 1 h and then cooled to -50° C. Tothe above mixture was added dropwise at -50° C. a solution of 4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-butylcarboxaldehyde (548mg, 2 mmol) in 10 ml of THF, and the mixture was stirred at -40°-50° C.for 1 h and then allowed to warm to 20° C. An aqueous ammonium chloridesolution was added to the mixture, and the resulting reaction mixturewas extracted with methylene chloride. The organic layer was dried oversodium sulfate and concentrated in vacuo. The residue was purified bysilica column chromatography (20 cm column, methylene chloride/methanol,30/1-10/1) followed by recrystallization from hot acetonitrile/ether toafford 425 mg (60%) of 2- 4-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-1-hydroxy-butyl!-1-methylimidazole,as a white crystalline solid, m.p.151°-154° C.

B. 2- 4-4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-1-phenoxythiocarbonyloxy-butyl!-1-methylimidazole

To a solution of 2- 4-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-1-hydroxy-butyl!-1-methylimidazole(690 mg, 1.94 mmol) in 30 ml of acetonitrile was added at 20° C. 473 mg(3.88 mmol) of DMAP and 403 mg (2.33 mmol) of phenyl chlorothioformate,and the mixture was stirred at 20° C. for 3 h. The solvent wasconcentrated in vacuo and the residue was partitioned between methylenechloride and an aqueous sodium bicarbonate solution. The organic layerwas dried over sodium sulfate and concentrated in vacuo. The residue waspurified by silica column chromatography (20 cm column, ethylacetate/hexane, 1/1-4/1) to afford 750 mg (78%) of 2- 4-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-1-phenoxythiocarbonyloxy-butyl!-1-methylimidazole,as a yellow oil.

C. 2- 4-4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-butyl!-1methylimidazole(I, Azo=1-methyl-2-imidazolyl, n=4, R₁,R₂ =3,5-dimethyl, R₃=2-methyl-tetrazol-5-yl)

To a solution of 2- 4-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-1-phenoxythiocarbonyloxy-butyl!-1-methylimidazole(1.94 mmol) in 35 ml of toluene was added AIBN (159 mg, 0.97 mmol) andn-tributyltin hydride (1.69 g), and the mixture was stirred at 75°-80°C. for 4 h. An aqueous sodium bicarbonate solution was added to themixture, and the mixture was extracted with ethyl acetate, and thenmethylene chloride (2×). The combined organic layer was dried oversodium sulfate and concentrated in vacuo. The residue was purified bysilica column chromatography (20 cm column, methylene chloride/methanol,30/1-15/1) to afford 440 mg (67%) of 2- 4-4-(2-methyltetrazol-5-yl)-2,6-dimethylphenoxy!-butyl!-1-methylimidazole,m.p. 100°-102° C. (from methylene chloride/hexane).

EXAMPLE 10

A. 2-Ethyl-1-methyl-5-tributyltin-imidazole

To a solution of 2-ethyl-1-methyl-5-imidazole (3.79 g, 34.5 mmol) in 120ml of ether was added 14.2 ml (35.5 mmol) of 2.5M butyllithium dropwiseat 20° C. The resulting mixture was stirred for 4 h, and then 11.78 g(36.2 mmol) of tributyltin chloride was added dropwise. The suspensionwas stirred overnight and an aqueous ammonium chloride solution wasadded. The organic layer was washed with brine, dried over sodiumsulfate, and concentrated in vacuo to afford 6.78 g (17.2 mmol, 49.8%)of 2-ethyl-1-methyl-5-tributyltin-imidazole.

B. Ethyl β-(2-ethyl-1-methyl-imidazol-5-yl)acrylate

To a solution of 2-ethyl-1-methyl-5-tributyltin-imidazole (17.2 mmol) in130 ml of xylene was added 4.28 g (18.9 mmol) of ethyl β-(iodo)acrylatefollowed by Pd(PPh₃)₄ (993 mg, 0.86 mmol). The mixture was heated at120° C. for 18 h under nitrogen, cooled, and water was added. Theorganic layer was separated and washed with 10% ammonium hydroxidesolution, and brine. The aqueous mixture was extracted with ethylacetate, and the combined organic layer was dried over sodium sulfateand concentrated in vacuo. The residue was purified by silicachromatography (20 cm silica column, ethyl acetate/hexane 1/1-2/1;methylene chloride/methanol 50/1-30/1) to yield 2.43 g (68%) of ethylβ-(2-ethyl-1-methyl-imidazol-5-yl)acrylate.

C. Ethyl 3-(1-methyl-2-ethyl-imidazol-5-yl)propionate

A mixture of ethyl β-(1-methyl-2-ethyl-imidazol-5-yl)acrylate (2.1 g,10.1 mmol) and 1.1 g of 10% Pd/C in ethyl acetate/ethanol/HCl (1M inethyl acetate; 50 ml/8 ml/8 ml) was hydrogenated under hydrogen (50 psi)for 2 h. The mixture was filtered through celite, the residue was washedwith ethylene chloride/methanol (5:1, 2×), and the combined organiclayer was concentrated in vacuo. The residue was basified with aqueoussodium bicarbonate solution, extracted with methylene chloride (4×), andthe combined organic layer was dried over sodium sulfate andconcentrated in vacuo. Upon chromatographic purification of the residueon 20 cm silica column (methylene chloride/methanol 50/1-15/1), 1.9 g(90%) of ethyl 3-(1-methyl-2-ethyl-imidazol-5-yl)propionate was isolatedas a yellow oil.

D. 5-(3-Hydroxypropyl)-1-methyl-2-ethylimidazole

To a cooled (0° C.) solution of ethyl3-(1-methyl-2-ethylimidazol-5-yl)propionate (1.75 g, 8:33 mmol) in 30 mlof THF was added 4.6 ml (4.6 mmol) of 1M LAH solution in THF at 0° C.After stirring at 0° C. for 15 min, the mixture was allowed to warm andstirred at 20° C. for 0.7 h. Rochelle salt solution (equiv) was addedand the mixture was stirred for 20 min. The aqueous mixture wasextracted with methylene chloride and filtered. The organic layer wasdried over sodium sulfate and concentrated in vacuo. The residue waspurified by chromatography on silica (10 cm column, methylenechloride/methanol, 6/1-6/1) followed by recrystallization fromacetonitrile/ether and methylene chloride/hexane to afford 1.268 g (90%)of 5-(3-hydroxypropyl)-1-methyl-2-ethylimidazole, as a white solid, m.p.69°-71° C.

E. 5- 3-4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!propyl!-1-methyl-2-ethylimidazole(I, Azo=1-methyl-2-ethylimidazol-5-yl, Y=1,3-propylene, R₁,R₂=3,5-dimethyl, R₃ =2-methyl-tetrazol-5-yl)

A mixture of 5-(3-hydroxypropyl)-1-methyl-2-ethylimidazole (150 mg, 0.89mmol), 4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenol (200 mg, 0.98mmol), and triphenylphosphine (257 mg, 0.98 mmol) was dissolved in 10 mlof THF under nitrogen at 0° C. To the above solution was added at 0° C.DEAD (170.5 mg, 0.98 mmol) and the mixture was stirred for 30 2 hallowing the mixture to warm to 20° C. The solvent was removed in vacuo,and the residue was purified by silica column chromatography (20 cmcolumn, ethyl acetate/hexane, 1/1-3/1; methylene chloride/methanol30/1-10/1) to afford 376 mg (quantitative) of 5- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1-methyl-2-ethyl-imidazole,as a white crystalline solid, m.p. 96°-98° C. (recrystallization frommethylene chloride/hexane).

F. 5- 3-4-(2-Methyl-tetrazol-5-yl)phenoxy!-propyl!-1-methyl-2-ethylimidazole (I,Azo=1-methyl-2-ethylimidazol-4-yl, Y=1,3-propylene, R₃=(2-methyltetrazol-5-yl), R₁ =R₂ =hydrogen)

A mixture of 5-(3-hydroxypropyl)-1-methyl-2-ethylimidazole (150 mg, 0.89mmol), 4-(2-methyl-tetrazol-5-yl)-phenol (172 mg, 0.98 mmol), and DEAD(171 mg, 0.98 mmol) was dissolved in 10 ml of THF under nitrogen at 0°C. To the above solution was added triphenylphosphine (257 mg, 0.89mmol) at 0° C. and the mixture was stirred for 2 h allowing the mixtureto warm to 20° C. The solvent was removed in vacuo, and the residue waspurified by silica column chromatography (20 cm column, ethylacetate/hexane, 1/1-3/1; methylene chloride/methanol 30/1-15/1) toafford 267 mg (92%) of 5- 3-4-(2-methyl-tetrazol-5-yl)phenoxy!propyl!-1-methyl-2-ethylimidazole, asa white crystalline solid, m.p. 115°-117° C. (recrystallization frommethylene chloride/hexane).

G. Compounds of the formula I wherein R₁ and R₂ are the same and are inthe 3,5 positions of the phenoxy ring, R₃ is 2-methyl tetrazolyl and Yis 1,3-propylene and AZO is X-(R₄, 1-methyl-imidazolyl)

The following were prepared using the methods described above.

    ______________________________________                                        Example   R.sub.1 = R.sub.2                                                                     R.sub.4     X   M.P.                                        ______________________________________                                        G1        CH.sub.3                                                                              H           5   100-102                                     G2        CH.sub.3                                                                              2 ethyl     4   55-57                                       G3        H       2 ethyl     4    99-101                                     G4        CH.sub.3                                                                              H           4   82-84                                       G5        H       H           4   122-124                                     ______________________________________                                    

EXAMPLE 11

A. 3-Methyl-5- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-thiazole (I,Azo=3-methylthiazol-5-yl, Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃=2-methyl-tetrazol-5-yl)

n-BuLi (2.5M, 1.33 ml, 3.33 mmol) was added slowly at -78° C. to asolution of 3-methyl-thiazole (300 mg, 3.03 mmol) in 8 ml of THF undernitrogen. After stirring at -78° C. for 15 min, HMPA (1.08 g, 6.06 mmol)was added and the resulting mixture was stirred for 10 min. To the abovemixture was added at -78° C. 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propylbromide (985 mg,3.03 mmol) in 5 ml of THF. The mixture was allowed to warm to 20° C. andstirred for 3 h. Saturated ammonium chloride solution was added and theaqueous layer was extracted with ether (3×), and the organic layer wasdried over sodium sulfate and concentrated in vacuo. The residue waspurified by silica column chromatography (15 cm column, ethylacetate/hexane, 1/8-3/1) to afford 290 mg (28%) of 3-methyl-5- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!thiazole.

EXAMPLE 12

A. 2- 4-(4-Cyano-2, 6-dimethylphenoxy)butyl!-dioxalane

To a mixture of 4-cyano-2,6-dimethylphenol (10.37 g, 70.6 mmol), 150 mlof NMP, potassium carbonate (10.2 g, 74 mmol), and 3.3 g (20 mmol) ofpotassium iodide was added 2-(3-chlorobutyl)-1,3-dioxalane (11.06 g,67.2 mmol) slowly, and the mixture was stirred at 75° C. overnight.After cooling, the mixture was poured into 1000 ml of water andextracted with ether (4×750 ml). The combined organic layer was washedwith 10% NaOH solution (3×100 ml), brine (170 ml), and dried over sodiumsulfate and filtered. The organic filtrate was concentrated in vacuo,and the residue was purified by silica column chromatography (10 cmcolumn, ethyl acetate/hexane, 1/5-1/1 ) to afford 17.8 g (96%) of 2-4-(4-cyano-2,6-dimethylphenoxy)butyl!-dioxalane, as a white solid, m.p.61°-62° C. (recrystallization from methylene chloride/hexane).

B. 5-(4-Cyano-2,6-dimethylphenoxy)pentyraldehyde

A mixture of 2- 4-(4-cyano-2, 6-dimethylphenoxy)butyl!dioxalane (4.6 g,16.7 mmol), 54 ml of acetic acid and 8 ml of water was stirred at 90° C.for 24 h. The solution was diluted with ice and basified with 35% NaOH,2N NaOH solution, and saturated sodium bicarbonate solution (pH=7). Theaqueous layer was extracted with ether (3×), the combined organic layerwas dried over sodium sulfaste and concentrated. The residue waspurified by silica column chromatography (20 cm column, methylenechloride/acetone, 1/0-100/1) to afford 3.1 g (80%) of5-(4-cyano-2,6-dimethylphenoxy)pentyraldehyde, as a white solid(recrystallization from ethyl acetate/hexane)

C. 5-(4-Cyano-2,6-dimethylphenoxy)-2-bromopentyraldehyde

A mixture of 5-(4-cyano-2,6-dimethylphenoxy)pentyraldehyde (1.7 g, 3.68mmol) and 5,5-dibromobarbituric acid (1.05 g, 3.68 mmol) in 90 ml of THFwas stirred at 75° C. for 26 h. The solvent was removed in vacuo, theresidue was redissolved in methylene chloride, filtered through a shortsilica column (8 cm, methylene chloride), and concentrated in vacuo toafford 2.15 g (94%) of5-(4-cyano-2,6-dimethylphenoxy)-2-bromopentyraldehyde, as a viscous oil.A sample was further purified by silica column chromatography (20 cm,methylene chloride/hexane, 1/1-1/10) followed by recrystallization fromethyl acetate/hexane to afford a white solid, m.p. 47°-49° C.

D. 5- 3-(4-Cyano-2,6-dimethylphenoxy)propyl!-2-methylthiazole

A mixture of 5-(4-cyano-2,6-dimethylphenoxy)-2-bromopentyraldehyde (1.8g, 6.4 mmol) and thioaceamide (0.48 g, 6.4 mmol) in 50 ml ofdichloroethane was stirred at 85° C. for 18 h. The solvent was removedin vacuo, an aqueous sodium bicarbonate solution was added to theresidue, and the aqueous layer was extracted with methylene chloride.The organic layer was dried over sodim sulfate, concentrated in vacuo,and the residue was purified by silica column chromatography (20 cmcolumn, ethyl acetate/hexane 1/5-1/1) to afford 1.2 g (72%) of 5-3-(4-cyano-2,6-dimethylphenoxy)propyl!-2-methylthiazole, as an oil whichwas crystallized from ethyl acetate/hexane to yield a yellow-whitesolid, m.p. 64°-66° C.

E. 5-3-(4-Aminohydroximinomethyl-2,6-dimethylphenoxy)propyl!-2-methylthiazol

Potassium carbonate (2.43 g, 17.58 mmol) was added to a stirred solutionof 815 mg (11.72 mmol) of hydroxylamine hydrochloride in 12 ml ofabsolute ethanol. The mixture was stirred at 80° C. for 15 min, then at20° C. for 45 min. To the above mixture was added 5-3-(4-cyano-2,6-dimethylphenoxy)propyl!-2-methylthiazole (837 mg, 2.93mmol) and the mixture was stirred at 80° C. for 16 h. The mixture wasfiltered, the residue was washed with hot ethanol, and the filtrate wasconcentrated in vacuo to yield 1.24 g of 5-3-(4-aminohydroximino-methyl-2,6-dimethylphenoxy)propyl!-2-methylthiazoleas a white solid.

F. 5- 3-4-(5-Methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-methylthiazole(Azo=2-methyl-5-thiazolyl,Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃ =5-methyl-1,2,4-oxadiazol-3-yl)

To a warm (45° C.) solution of 5-3-(4-aminohydroximinomethyl-2,6-dimethylphenoxy)propyl!-2-methylthiazole(308 mg, 0.8 mmol)) in 5 ml of pyridine was added 126 mg (1.6 mmol) ofacetyl chloride dropwise, and the resulting mixture was stirred at 110°C. for 16 h, cooled, and diluted with water. The mixture was extractedwith ether (4×), and the organic layer was washed with water and driedover sodium sulfate. The organic layer was concentrated in vacuo and aresidue was purified by silica column chromatography (20 cm, ethylacetate/hexane, 1/5-4/1) to afford 182 mg (66%) of 5- 3-4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-methylthiazole,as white crystalline solids, m.p. 60°-62° C.

G. 5- 3-4-(5-Trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-methylthiazole(Azo=2-methyl-5-thiazolyl,Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃=5-trifluoromethyl-1,2,4-oxadiazol-3-yl)

To a solution of 5-3-(4-aminohydroximino-methyl-2,6-dimethylphenoxy)propyl!-2-methylthiazole(593 mg, 1.54 mmol)) in 10 ml of pyridine was added at 20° C. 645 mg(3.07 mmol) of trifluoroacetic anhydride dropwise, and the resultingmixture was stirred at 110° C. for 40 h. The solvent was removed invacuo, the residue cooled, and diluted with water. The mixture wasextracted with ether (3×), and the organic layer was dried over sodiumsulfate. The organic layer was concentrated in vacuo and a residue waspurified by silica column chromatography (20 cm, ethyl acetate/hexane,1/10-1/3) to afford 256 mg (42%) of 5- 3-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-methylthiazole,as white crystalline solids, m.p. 62°-64° C. (recrystallization fromethyl acetate/hexane).

H. 5- 3-4-(5-Difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-methylthiazole(Azo=2-methyl-5-thiazolyl,Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃=5-difluoromethyl-1,2,4-oxadiazol-3-yl)

A mixture of 5-3-(4-aminohydroximino-methyl-2,6-dimethylphenoxy)propyl!-2-methylthiazole(1.12 g, 3.5 mmol)) in 14 ml of NMP and 7 ml of ethyl difluoroacetatewas stirred at 105° C. for 16 h. The mixture was cooled, partiallyconcentrated in vacuo, and diluted with water. The mixture was extractedwith ether (3×), and the organic layer was dried over sodium sulfate.The organic layer was concentrated in vacuo and a residue was purifiedby silica column chromatography (20 cm, ethyl acetate/hexane, 1/10-1/1)to afford 520 mg (39%) of 5- 3-4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-methylthiazole,as white needles (from methylene chloride/hexane).

EXAMPLE 13

A. 5- 3-(4-Cyano-2,6-dimethylphenoxy)propyl!-2-ethylthiazole

A mixture of 5-(4-cyano-2,6-dimethylphenoxy!-2-bromopentyraldehyde (310mg, 1 mmol) and thiopropionamide (98 mg, 1.1 mmol) in 8 ml ofdichloroethane was stirred at 85° C. for 16 h. The solvent was removedin vacuo, an aqueous sodium bicarbonate solution was added to theresidue, and the aqueous layer was extracted with methylene chloride(3×). The organic layer was dried over sodium sulfate, concentrated invacuo, and the residue was purified by silica column chromatography (20cm column, ethyl acetate/hexane 1/5-1/1) to afford 246 mg (82%) of 5-3-(4-cyano-2,6-dimethylphenoxy)propyl!-2-ethylthiazole, m.p. 52°-53° C.

B. 5-3-(4-Aminohydroximinomethyl-2,6-dimethylphenoxy)propyl!-2-ethylthiazole

Potassium carbonate (4.97 g, 36 mmol) was added to a stirred solution of1.67 g (24 mmol) of hydroxylamine hydrochloride in 24 ml of absoluteethanol. The mixture was stirred at 80° C. for 15 min, then at 20° C.for 45 min. To the above mixture was added 5-3-(4-cyano-2,6-dimethylphenoxy)propyl!-2-ethylthiazole (1.8 g, 6 mmol)and the mixture was stirred at 80° C. for 18 h. The hot mixture wasfiltered, the residue was washed with hot ethanol, and the filtrate wasconcentrated in vacuo to yield 2.18 g of 5-3-(4-aminohydroximino-methyl-2,6-dimethylphenoxy)propyl!-2-ethylthiazole as a white solid.

C. 5- 3-4-(S-Trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-ethylthiazole(Azo=2-ethyl-5-thiazolyl,Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃=5-trifluoromethyl-1,2,4-oxadiazol-3-yl)

To a solution of 5-3-(4-aminohydroximino-methyl-2,6-dimethylphenoxy)propyl!-2-methylthiazole(800 mg, 2.4 mmol)) in 16 ml of pyridine was added at 20° C. 1.008 g(4.8 mmol) of trifluoroacetic anhydride dropwise, and the resultingmixture was stirred at 20° C. for 5 h, and then at 110° C. for 40 h. Thesolvent was removed in vacuo, the residue cooled, and diluted withwater. The mixture was extracted with ether (3×), and the organic layerwas dried over sodium sulfate. The organic layer was concentrated invacuo and a residue was purified by silica column chromatography (20 cm,ethyl acetate/hexane, 1/10-1/3) to afford 333 mg (34%) of 5- 3-4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-ethylthiazole,as white crystalline solids, m.p. 57°-59° C. (recrystallization fromethyl acetate/hexane).

D. 5- 3-4-(5-Methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-ethylthiazole(Azo=2-ethyl-5-thiazolyl,Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃ =5-methyl-1,2,4-oxadiazol-3-yl)

To a solution of 5-3-(4-aminohydroximino-methyl-2,6-dimethylphenoxy)propyl!-2-methylthiazole(308 mg, 0.8 mmol)) in 6 ml of pyridine was added 200 mg (0.6 mmol) ofacetyl chloride dropwise at 20° C., and the resulting mixture wasstirred at 110° C. for 18 h, cooled, and diluted with water. The mixturewas extracted with ether (3×), the organic layer was washed with waterand dried over sodium sulfate. The organic layer was concentrated invacuo and a residue was purified by silica column chromatography (20 cm,ethyl acetate/hexane, 1/5-2/1) to afford 135 mg (63%) of 5- 3-4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-ethylthiazole,as white crystalline solids, m.p. 43°-45° C.

E. 5- 3-4-(5-Difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-ethylthiazole(Azo=2-ethyl-5-thiazolyl,Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃=5-difluoromethyl-1,2,4-oxadiazol-3-yl)

A mixture of 5-3-(4-aminohydroximino-methyl-2,6-dimethylphenoxy)propyl!-2-ethylthiazole(600 mg, 1.8 mmol)) in 7.2 ml of NPM and 3.6 ml of ethyl difluoroacetatewas stirred at 105° C. for 19 h. The mixture was cooled, partiallyconcentrated in vacuo, and diluted with water. The mixture was extractedwith ether (3×), and the organic layer was dried over sodium sulfate.The organic layer was concentrated in vacuo and a residue was purifiedby silica column chromatography (20 cm, ethyl acetate/hexane, 1/10-1/1)to afford 297 mg (42%) of 5- 3-4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-2-ethylthiazole,as a white solid, m.p. 68°-70° C.

F. 5- 3-(4-Cyano-2,6-dimethylphenoxy)propyl!-thiazole

To a mixture of phosphorus pentasulfide (760 mg, 1.71 mmol) and 8 ml ofdioxane was added rapidly dropwise formamide (570 mg, 12.67 mmol), andthe mixture was stirred at 65° C. for 10 min and cooled. To the abovemixture was added in portions5-(4-cyano-2,6-dimethylphenoxy!-2-bromopentyraldehyde (2.62 g, 8.45mmol), and the mixture was stirred at 65° C. for 20 min and thenrefluxed for 60 min. After adding 5 ml of water and 1 ml of conc. HClthe mixture was refluxed another hour. The above mixture was basifiedwith 2N NaOH solution and sodium bicarbonate solution (to pH=8). Theaqueous layer was extracted with methylene chloride, the organic layerwas dried over sodium sulfate, and concentrated in vacuo. The residuewas purified by silica column chromatography (20 cm column, ethylacetate/hexane 1/5-1/1) to afford 1.11 g (48%) of 5-3-(4-cyano-2,6-dimethylphenoxy)propyl!-thiazole, as an oil which wascrystallized from ethyl acetate/hexane to yield a white solid, m.p.71°-73° C.

G. 5- 3-(4-Aminohydroximinomethyl-2,6-dimethylphenoxy)propyl!-thiazole

Potassium carbonate (3.07 g, 22.3 mmol) was added to a stirred solutionof 1.03 g (14.8 mmol) of hydroxylamine hydrochloride in 15 ml ofabsolute ethanol. The mixture was stirred at 80° C. for 15 min, then at20° C. for 45 min. To the above mixture was added 5-3-(4-cyano-2,6-dimethylphenoxy)propyl!-thiazole (1.01 g, 3.71 mmol) andthe mixture was stirred at 80° C. for 20 h. The mixture was filtered,the residue was washed with hot ethanol, and the filtrate wasconcentrated in vacuo to yield 1.26 g of 5-3-(4-aminohydroximino-methyl-2,6-dimethylphenoxy)propyl!thiazole as awhite solid.

H. 5- 3-4-(5-Trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-thiazole(Azo=5-thiazolyl,Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃=5-trifluoromethyl-1,2,4-oxadiazol-3-yl)

To a solution of 5-3-(4-aminohydroximino-methyl-2,6-dimethylphenoxy)propyl!-thiazole (450mg, 1.48 mmol)) in 15 ml of pyridine was added 620 mg (2.95 mmol) oftrifluoroacetic anhydride dropwise. The resulting mixture was stirred at20° C. for 2 h, and then at 110° C. for 18 h. The solvent was removed invacuo, the residue diluted with water, and the mixture was extractedwith ether (3×). The organic layer was dried over sodium sulfate,concentrated in vacuo and a residue was purified by silica columnchromatography (20 cm, ethyl acetate/hexane, 1/8-1/2) to afford 190 mg(34%) of 5- 3- 4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-26-dimethylphenoxy!-propyl!-thiazole, as white crystalline solids, m.p.95°-97° C.

I. 5- 3-4-(5-Difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!-thiazole(Azo=5-thiazolyl,Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃=5-difluoromethyl-1,2,4-oxadiazol-3-yl)

A mixture of 5-3-(4-aminohydroximino-methyl-2,6-dimethylphenoxy)propyl!-thiazole (506mg, 1.66 mmol), 5 ml of NMP and 3.3 ml fo ethyl difluoroacetate wasstirred at 105° C. for 20 h. The solvent was partially removed in vacuo,the residue was cooled and diluted with water. The mixture was extractedwith ether (3×), and the organic layer was dried over sodium sulfate.The organic layer was concentrated in vacuo and a residue was purifiedby silica column chromatography (20 cm, ethyl acetate/hexane, 1/5-1/2)to afford 212 mg (35%) of 5- 3-4-(5-difluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy!-propyl!thiazole,as white crystalline solids, m.p. 78°-80° C. (recrystallization fromethyl acetate/hexane).

EXAMPLE 14

A. 2- 4- 4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!butyl!-dioxalane

To a mixture of 4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenol (7.54 g,37 mmol), 75 ml of NMP, potassium carbonate (5.1 g, 37 mmol), and 1.67 g(10 mmol) of potassium iodide was added 2-(4-chlorobutyl)-1,3-dioxalane(5.53 g, 33.6 mmol) dropwise, and the mixture was stirred at 80° C.overnight. After cooling, the mixture was poured into 500 ml of water,and extracted with ether (4×125 ml). The combined organic layer waswashed with 10% NaOH solution(5×100 ml), brine (80 ml), and dried oversodium sulfate and filtered. The organic filtrate was concentrated invacuo, and the residue was purified by recrystallization from methylenechloride/hexane to afford 6.78 g (61%) of 2- 4-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-butyl!-dioxalane. Theproduct was further purified by silica column chromatography (12 cm,ethyl acetate/hexane, 1/5-1/2) followed by recrystallization frommethylene chloride/hexane, m.p. 57°-59° C.

B. 5- 4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!pentylaldehyde

2- 4- 4-(2-Methyl-tetrazol-5-yl)-2, 6-dimethylphenoxy!butyl!-dioxalane(4.3 g, 12.95 mmol) was dissolved in 42 ml of acetic acid and 5 ml ofwater and the mixture was stirred at 90° C. for 24 h. The solution withice was basified with 35% NaOH solution, 2N NaOH solution, and sodiumbicarbonate solution (to pH=7). The above mixture was extracted withether (3×), and the combined organic layer was dried over sodium sulfateand concentrated. The residue was purified by silica columnchromatography (methylene chloride/acetone, 1/0-50/1) followed byrecrystallization from methylene chloride/hexane to afford 2.4 g (64%)of 5- 4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxyl!-pentylaldehyde,m.p. 50°-52° C.

C. 5-4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-2-bromopentyl-aldehyde

A mixture of 5-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!pentylaldehyde (1.94 g,9.74 mmol) and 5,5-dibromobarbituric acid (0.96 g, 3.37 mmol) in 80 mlof ether was stirred at 20° C. for 20 h. The mixture was filtered andthe residue was washed with ether (2×). The combined organic layer wasdried over sodium sulfate, concentrated in vacuo, and the residue waspurified by silica column chromatography (12 cm, methylenechloride/acetone, 1/0-50/1) followed by recrystallization from methylenechloride/hexane to afford 1.69 g (68%) of 5-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxyl-2-bromopentyl-aldehyde,as a white solid, m.p. 62°-64° C.

D. 5- 3-4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!propyl!-2-methylthiazole(I, Azo=2-methyl-5-thiazolyl, Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃=2-methyltetrazol-5-yl)

A mixture of 5-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-2-bromo-pentylaldehyde(367 mg, 1 mmol) and thioaceamide (68 mg, 0.9 mmol) in 10 ml ofdichloroethane was stirred at 85° C. for 22 h. The solvent was removedin vacuo, an aqueous sodium bicarbonate solution was added to theresidue, the aqueous layer was extracted with methylene chloride. Theorganic layer was dried over sodium sulfate, concentrated in vacuo, andthe residue was purified by silica column chromatography (20 cm column,ethyl acetate/hexane 1/5-4/1) followed by recrystallization frommethylene chloride/hexane to afford 214 mg (70%) of 5- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-2-methylthiazole,as an oil which was crystallized from ethyl acetate/hexane to yield ayellow-white solid, m.p. 86°-88° C.

EXAMPLE 15

A compound of formula I wherein (AZO) is triazine was prepared by thefollowing route: ##STR7##

E. By replacing H₂ NNH CSNH₂ in the formation of example 19C, with H₂NNC(CH₃)-NH₂ one obtains an intermediate which, upon heating intriethylamine, forms a compound of formula I, m.p. 86°-88° C. (23%)(AZO=5-(3-methyl)1,2,4-triazinyl, Y=1,3-propyl, R₁,R₂ =3,5-dimethyl, R₃=5-difluoromethyl 1,2,4-oxadiazol-3-yl.

F. Using the method of 19E but substituting the appropriate hydrazinylreactant one obtains compounds of formula I wherein Y=1,3-propylene,R₁,R₂ =3,5-dimethyl, R₃ =5-difluoromethyl-1,2,4-oxadiazolyl,AZO=5-(3-ethyl)-1,2,4-triazinyl m.p. 85°-87° C. (23% yield).

G. Using the method of example 11E but replacing the staring material of11A with 4-(3-acetyl-propyloxy)-3,5-dimethyl benzonitrile one obtains anintermediate which, when reacted with hydroxyl amine and thentrifluoroacetic an hydride in pyridine (as described above) one obtainsa compound of formula I wherein AZO=5-(3-methyl)-1,2,4-triazinyl;Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃=5-trifluoromethyl-1,2,4-oxadiazol-3-yl); (50% yield).

EXAMPLE 16 5-4-(5-Methyl-1,2,4-oxadiazol-3-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole(AZO-Y-=5-methyl-1,2,4-oxadiazol-3-yl)propyl,R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

A solution of sodium methoxide (prepared under argon from 56 mg (1.2 eq)of sodium and 2 ml of methanol) was added to a stirred solution of 166mg (1.2 eq) of hydroxylamine hydrochloride in 2 ml of methanol underargon. The mixture was stirred for 1 h at room temperature, 540 mg (20mmol) of 5- 4-(3-cyano)propyloxy-3,5-dimethyl!phenyl-2-methyltetrazolewas added and the resulting mixture was allowed to reflux for 26 h.After adding an additional mixture of sodium methoxide (180 mg of Na in5 ml of methanol) and hydroxylamine hydrochloride (520 mg; 7.8 mmol),the resulting reaction mixture was allowed to reflux overnight. Themixture was filtered, the filtrate concentrated in vacuo, and theresidue (800 mg) was purified by a flash column chromatography (75 mg ofsilica gel; 25% of methanol in methylene chloride) to afford 270 mg(44%) of 5-4-(3-aminohydroxyiminomethyl)-propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole.

To a solution of 440 mg (1.45 mmol) of 5-4-(3-aminohydroxyiminomethyl)-propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazole in 3 ml of pyridine (with stirringand slight warming) was added rapidly dropwise 0.21 ml (2.84 mmol) ofacetyl chloride and the resulting mixture was gently refluxed for 2 h.The reaction mixture was cooled, diluted with water, chilled on icebath, and the solids were filtered and washed with excess water (150 ml)to remove pyridine. The solid product was dissolved in methylenechloride, dried over magnesium sulfate, filtered through a florisil pad,and the organic layer was concentrated in vacuo to yield 270 mg of a tansolid. The tan solid product was purified through MPLC column (120 gKeiselgel, 50% ethyl acetate/hexane, 25 ml fractions, 25 ml/min), andrecrystallization from methanol to afford 210 mg (44.7%) of 5-4-(5-methyl-1,2,4-oxadiazol-3-yl)propyloxy-3,5-dimethyl!phenyl-2-methyl-tetrazoleas clear crystalline solid, m.p. 105.5°-106.5° C.

EXAMPLE 17

A. 3- 4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!propylbromide

A mixture of (3-hydroxypropyl)-bromide (2.17 ml, 24 mmol),4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenol (5.1 g, 25 mmol), and DEAD(4.18 g, 24 mmol) was dissolved in 50 ml of THF at 0° C. To the abovesolution was added dropwise triphenylphosphine (6.3 g, 24 mmol) at 0° C.and the mixture was allowed to stir at 0° C. for 0.5 h. The mixture wasdiluted with 500 ml of water and 100 ml of ether, and the aqueous layerewas extracted with ether (2×400 ml). The combined organic layer wasdried over sodium sulfate, and concentrated in vacuo. The residue wasdissolved in 800 ml of ether, and the organic layer was washed with 10%NaOH solution (3×50 ml), dried over sodium sulfate, and concentrated invacuo. The residue was purified by silica column chromatography (7 cmcolumn, ethyl acetate/hexane, 1/5) followed by recrystallization frommethylene chloride/hexane to afford 6.4 g (82%) of 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxyl!-propylbromide, as alight yellow oil.

B. 5-Carbomethoxy-2- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole(I, Azo=5-carbomethoxy-1,2,4-triazol-2-yl, Y=1,3-propylene, R₁,R₂=3,5-dimethyl, R₃ =2-methyl-tetrazol-5-yl)

Hexane washed 60% NaH (22 mg, 0.55 mmol) in 0.5 ml of DMF was added at20° C. to a solution of 5-carbomethoxy-1,2,4-triazole (63.5 mg, 0.5mmol) in 0.5 ml of DMF and the mixture was stirred for 1 h. To the abovemixture was added at 20° C. 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propylbromide (163 mg,0.5 mmol) in 0.5 ml of DMF and the mixture was stirred at 20° C. for 18h. The mixture was partitioned between ice/water and ethyl acetate. Theaqueous layer was extracted with ethyl acetate (3×), and the organiclayer was dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica column chromatography (20 cm column,ethyl acetate/hexane, 1/5-1/0; methylene chloride/acetone) to afford 74mg (40%) of 5-carbomethoxy-2- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole.

C. 5-Hydroxymethyl-2- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole(I, Azo=5-hydroxymethyl-1,2,4-triazol-2-yl, Y=1,3-propylene, R₁,R₂=3,5-dimethyl, R₃ =2-methyl-tetrazol-5-yl)

To a solution of 5-carbomethoxy-2- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole(37.1 mg, 0.1 mmol) in 1 ml of THF was added at 0° C. a solution of 1MLAH in THF (65 ul, 1M in THF, 0.065 mmol). The mixture was stirred for10 min at 0° C. and then stirred at 20° C. for 24 h. Rochelle saltsolution was added to the mixture and the solution was stirred at 20° C.for 10 min. Ethyl acetate was added to the above mixture, the aqueouslayer was extracted with methylene chloride (3×), and the combinedorganic layer was dried over sodium sulfate and concentrated in vacuo.The residue was purified by silica column chromatography (10 cm column,ethyl acetate/hexane, 1/1-1/0; methylene chloride/acetone, 2/1-1/2) toafford 27 mg (79%) of 5-hydroxymethyl-2- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole,as a white solid.

D. 5-Phenoxythiocarbonyloxymethyl-2- 3- 4-(2-methyltetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole

To a mixture of 5-hydroxymethyl-2- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethyl-phenoxy!-propyl!-1,2,4-triazole(343 mg, 1 mmol) in 15 ml of acetonitrile was added DMAP (244 mg, 2mmol) and phenyl chlorothioformate (381 mg, 2.2 mmol). The mixture wasstirred at 20° C. for 7 h, an additional phenyl chlorothioformate (1equiv) was added, and the mixture was stirred for 15 h. The solvent wasremoved in vacuo and 5-phenoxythiocarbonyloxymethyl-2- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazolewas isolated and used without further purification.

E. 5-Methyl-2- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole(I, Azo=5-methyl-1,2,4-triazol-2-yl, Y=1,3-propylene, R₁,R₂=3,5-dimethyl, R₃ =2-methyl-tetrazol-5-yl)

To a solution of 5-phenoxythiocarbonyloxymethyl-2- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole(130 mg, 0.79 mmol) in 20 ml of toluene was added AIBN (130 mg, 0.79mmol) and tributyltin hydride (3.2 g, 11 mmol) and the mixture wasstirred at 75° C. for 6.5 h. The solvent was concentrated in vacuo andthe residue was purified by silica column chromatography (10 cm column,ethyl acetate/hexane, 1/1-5/1; methylene chloride/acetone, 4/1-0/1) toafford 142 mg (43%) of 5-methyl-2- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole,m.p. 101°-103° C.

F. 2- 3- 4-(2-Methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!propyl!-1,2,4-triazole (I, Azo=1,2,4-triazol-2-yl,Y=1,3-propylene, R₁,R₂ =3,5-dimethyl, R₃ =2-methyltetrazol-5-yl)

To a solution of 5-carbomethoxy-1- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole(868 mg, 2.34 mmol) in 23 ml of THF was added dropwise at 0° C. asolution of 1M LAH in THF (1.52 ml, 1.52 mmol). The mixture was stirredfor 20 min at 0° C. and then stirred at 20° C. for 24 h. Rochelle saltsolution was added to the mixture and the solution was stirred at 20° C.for 10 min. Ethyl acetate was added to the above mixture and the aqueouslayer was extracted with methylene chloride (3×). The combined organiclayer was dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica column chromatography (16 cm column,methylene chloride/acetone, 8/1-0/1) to afford 132 mg (18%) of 2 - 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!propyl!-1,2,4-triazole,m.p. 76°-78° C.

G. 5-Phenoxythiocarbonyloxymethyl-1- 3-4-(2-methyletrazol-5-yl)-2,6dimethylphenoxy!-propyl!-1,2,4-triazole

To a mixture of 5-hydroxymethyl-1- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethyl-phenoxy!-propyl!-1,2,4-triazole(343 mg, 1 mmol) in 15 ml of acetonitrile was added DMAP (244 mg, 2mmol) and phenyl chlorothioformate (381 mg, 2.2 mmol). The mixture wasstirred at 20° C. for 7 h. An additional phenyl chlorothioformate (1equiv) was added, and the mixture was stirred for 15 h. The solvent wasremoved in vacuo and 5-phenoxythiocarbonyloxymethyl-1- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazolewas isolated and used without further purification.

H. 5-Methyl-1- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!3-propyl!-1,2,4-triazole(I, Azo=5-methyl-1,2,4-triazol-1-yl, Y=1,3-propylene, R₁,R₂=3,5-dimethyl, R₃ =2-methyl-tetrazol-5-yl) p To a solution of5-phenoxythiocarbonyloxymethyl-1- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole(130 mg, 0.79 mmol) in 20 ml of toluene was added AIBN (130 mg, 0.79mmol) and tributyltin hydride (3.2 g, 11 mmol) and the mixture wasstirred at 75° C. for 6.5 h. The solvent was concentrated in vacuo andthe residue was purified by silica column chromatography (13 cm column,ethyl acetate/hexane, 1/1-5/1; methylene chloride/acetone, 4/1-0/1) toafford 61 mg (19%) of 5-methyl-1- 3-4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy!-propyl!-1,2,4-triazole,m.p. 126°-128° C.

EXAMPLE 18A

2.38 g of 2-methyl-5-(3,5-dimethyl-4-33-methylisoxazol-5-yl!propoxyphenyl)-tetrazol was dissolved in 60 mL ofmethanol with 2.29 g of ammonium formate and 0.24 g of palladium oncarbon and stirred overnight. The mixture was filtered through celitewhile washing with methanol. The filtrate was concentrated to a greysolid (2.35 g) The solid was extracted with ether and dried over sodiumsulfate and was concentrated to a light green solid 1.74 g (73%) of thecorresponding β-methyl, β-amino α-unsaturated keto compound which wasused without further purification.

The product from preparation above was dissolved in 15 mL of ethanol and0.3 mL of methylhydrazine was added and the reaction mixture heated to60° C. overnight. The reaction mixture was concentrated to a pale yellowsolid and purified by MPLC (45 to 65% EtOAc/hexane). Two products wereobtained, A₁, a product according to formula I wherein; azo is1,5-dimethyl-3-pyrazolyl, Y=1,3-propylene, R₁, R₂ representes3,5-dimethyl, R₃ =2-methyltetrazol-yl, (m.p. 77°-78°, 0.206 g). Theother product, A₂, was obtained in purified form from recrystallizationin ethylacetate in hexane, (m.p. 80°-81C.), 0.115 g was a compound offormula I wherein azo is 1,3-dimethyl-5-pyrazolyl, Y=1,3-propylene, R₁,R₂ represents 3,5-dimethyl, R₃ =2-methyl-5-tetrazol-yl.

EXAMPLE 18B-E

Using the method described above compounds of formula I ere preparedwhere R₃ is 2-methyl-5-tetrazolyl; R₁, R₂ represents 3,5-dimethyl, Y is1,3-propylene and AZO is 3-(R₄, R₅) pyrazylyl.

    ______________________________________                                        Ex.     R.sub.4       R.sub.5 M.P.                                            ______________________________________                                        18b     5-CH.sub.3    H       67-69                                           18c     1-CH.sub.3    H       110-111                                         18d     H             H       --                                              18e     5-CH.sub.3    2-CH.sub.3                                                                            80-81                                           ______________________________________                                    

EXAMPLE 18F

9 g of 3-(4-bromo-2,6-dimethylphenoxy)propyl!vinylmethylether and 110 mLof triethylorthoformate and 12 mls of boron trifluoride etherate withexcess Na₂ CO₃ was refluxed. Upon cooling the reaction mixture wasstirred for 24 hours. After no further gas evolution was observed, thereaction was stirred for 4 additional hours at room temperature.Finally, the reaction mixture was filtered through a glass frittedfunnel, the filtrate was concentrated under vacuum yielding 9 g or anoil used in the next step.

To the product obtained above 6.2 g of ethylhydrazine oxalate was addedand the mixture refluxed for 24 hours under nitrogen. The reactionmixture was concentrated under vacuum and purified via MPLC to providethe corresponding 1-ethyl-3-(4-bromo-2,6-dimethylphenoxy)propylpyrazolyl. (yield 32%, 2.2 g).

1.68 g of the product obtained above was combined with 0.446 g ofcopper/cyanide in DMF and refluxed for 48 hours. The mixture was dilutedwith 100 mls of an ethyl acetate/water mixture and filtered. The mixturewas washed with water, then saturated amoniumchloride and dried overmagnesium sulfate, filtered and concentrating yielding 1.2 g of thecorresponding cyanide product.

The cyanide obtained above was combined with hydroxylamine hydrochlorideand potassium carbonate ethanol and refluxed under nitrogen for 3 days.On work-up as described above, the product was then exposed todifluoroethylacetate resulting in the formation of ta compound offormula I, m.p. 40°-50° C; 114 mgs (R₁, R₂ =3,5-dimethyl,Y=1,3-propylene, azo=1-ethyl-4-pyrazolyl, R₃=5-difluoromethyl-1,2,4-oxadiazol-3-yl).

EXAMPLE 18G

Using any of the compounds disclosed in U.S. Pat. No. 5,349,068 it iscontemplated that any corresponding compound of formula I can beprepared by the method of Example 18A.

EXAMPLE 19A

1.525 g of 4-(3,5-dimethyl- 2-methyl-5-tetrazolyl!phenoxy)-propionicacid was purified by dissolving the acid in a mixture of 3 mmol sodiumhydroxide and washing several times with ethylacetate to remove anyimpurity. The basic phase was then acidified with concentratedhydrochloric acid to a pH of about 3. A white crystaline solid wasfiltered and dried to give the purified acid used in the next step.

The acid purified above was dissolved in methylene chloride and 5 mls ofthionylchloride was added and the mixture was refluxed for 6 hours. Thereaction mixture was then concentrated under vacuum to yield a whitesolid (m.p. 81°-82° C.). The resulting acid chloride was used in thenext step without purification.

Acid chloride from above was dissolved in 50 mL of toluene and 0.34 g ofacetichydrazide and 5 drops of triethylamine was added and heated to 90°C. for 8 hours. The resulting reaction mixture was extracted with ethylacetate, washed with brine, dried over sodium sulfate and concentratedto an off white solid, yielding 1.54 g of the corresponding amide incrude form. This crude product was recrystallized from ether and hexaneyielding 0.5 g (32%) of the corresponding amide product.

5 g of 4-hydroxy-3,5-dimethyl-benzonitrile was dissolved in 120 mL ofNMP and 5.86 g of K₂ CO₃ and 0.58 g of KI and 4.8 mL ofethylbromobutyrate was heated to 60° C. for 24 hours. Upon cooling,water was added and an off white precipitate formed. After washing theprecipitate with water, 8.90 g (quantitative) of the product wasobtained.

The ethyl/ester obtained above was dissolved in 0.82 g of LiOH in anethanol/water mixture (4:1-120 mls). The reaction mixture was stirred atroom temperature, the ethanol was removed by vacuum concentration andthe resulting solid product was washed with ether, and then acidifiedand a white solid was filtered off yielding 6.934 g (88%) of thecorresponding acid.

3.9 g of the acid obtained above was dissolved in 120 mls of methylenechloride and 6.0 mls of SOCl₂ was heated to reflux for 3 hours. Thereaction mixture was allowed to cool and stand over night uponconcentration it yielded a yellow oil. To this oil was added a 120 mlsof THF and 1.22 g of acetic hydrazide with 5 drops of triethylamine. Thereaction mixture was refluxed for three hours, a white percipitate wasfiltered off and washed with water, dried under high vacuum to yield3.50 g (72%) of the corresponding 2-methyl-1,3,4-oxadiazol-5-ylcompound.

The compound obtained above (azo=2-methyl-1,3,4-oxadiazol-5-yl,Y=1,3-propyl, R₁, R₂ =3,5-dimethyl, R₃ =CN) was dissolved in 100 mls ofethanol and NH₂ OH-HCl and K₂ CO₃ (2.75 g), the mixture was stirred atroom temperature for 46 hours. Off white solids appeared in the flask,these were washed with ethanol, yielding 1.37 g of crude material usedin the next step.

This material was dissolved in 15 mL of pyridine and 0.85 mL oftrifluoroacetic anhydride was added and the mixture was heated to 80° C.for 3 hours. The reaction mixture was allowed to cool, water was addedand the mixture was extracted with methylene chloride and washed withacid and then salt, dried over sodium sulfate and purified by MPLC (50%)ethyl acetate/hexanes. A white solid was obtained and was dried underhigh vacuum to 0.176 g m.p. 53°-54° C., (Formula I,azo=2-methyl-1,3,4-oxadiazol-5-yl, Y=1,3-propylene, R₁, R₂=3,5-dimethyl, R₃ =3-trifluoromethyl-1,2,4-oxadiazol-3-yl).

EXAMPLE 19B

Using the methods described above, a compound of formula I withAZO-Y=3-(5-methyl-1,3,4-oxadiazol-2-yl) propyl and R₁, R₂ =3,5-dimethyl,R3=2-methyl-5-tetrazolyl was prepared, m.p. 74°-76° C.

EXAMPLE 20

As further examples, phenols described only generally thus far can bereacted with any known ω-(Azo)-alkanol, or ω-(Azo)-alkylhalide includingany of those described hereinabove using the methods previouslydescribed herein to provide a compound of formula I. It is contemplatedthat any phenol disclosed in allowed application Ser. No. 07/869,287,incorporated herein by reference, is also useful in forming a compoundof formula I, using the methods described above. For the reader'sconvenience the same nomenclature conventions described herein forcompounds of formula I are adhered to for phenol intermediates listedbelow, and a literature reference describing the known phenol isincluded.

    ______________________________________                                                                            Reference                                                                     U.S.                                      R.sub.1   R.sub.2  R.sub.3          Pat. No.                                  ______________________________________                                        H         H        1,2,4-oxadiazol-2yl                                                                            4,857,539                                 H         H        4,2-dimethyl-2-thiazolyl                                                                       4,857,539                                 H         H        2-benzoxazolyl   4,857,539                                 3,5 dichloro       3-furanyl        4,857,539                                 3,5 dichloro       2-furanyl        4,857,539                                 3,5 dichloro       2-thienyl        4,857,539                                 3,5 dichloro       2-pyridinyl      4,857,539                                 3,5 dichloro       1-methyl-1H-pyrrol-2yl                                                                         4,857,539                                 3,5 dichloro       3-thienyl        4,857,539                                 3,5 dichloro       4-pyridinyl      4,857,539                                 3 nitro   H        benzothiazol-2-yl                                                                              4,857,539                                 H         H        2-(4,5-dihydro-4 4,843,087                                                    methyl)oxazolyl                                            3 methyl  H        2-oxazolyl       4,843,087                                 3 bromo   H        2-oxazolyl       4,843,087                                 3,5 dimethyl       3-methyl-5-isoxazolyl                                                                          4,843,087                                 2,6 dimethyl       3-methyl-5-isoxazolyl                                                                          4,843,087                                 H         H        5-methyl-3-isoxazolyl                                                                          4,942,241                                 H         H        4-hydroxy phenyl (Aldrich)                                 H         H        phenyl           (Aldrich)                                 H         H        5-ethyl-thiazol-2-yl                                                                           5,100,893                                 H         H        4,5-dimethyl-thiazol-2-yl                                                                      5,100,893                                 H         H        2-ethyl-thiazol-4-yl                                                                           5,100,893                                 H         H        5-ethyl-1,3,4-thiadiazol-2-yl                                                                  5,100,893                                 H         3-Cl     3-ethyl-1,2,4-oxadiazol-5-yl                                                                   5,100,893                                 H         H        3-cyclopropyl-1,2,                                                                             5,100,893                                                    4-oxadiazol-5-yl                                           H         H        3-tbutyl-1,2,4-oxadiazolyl                                                                     5,100,893                                 H         H        5-ethyl-1,3,4-oxadiazol-2-yl                                                                   5,100,893                                 H         H        3-cyclopropyl,2, 5,100,893                                                    4-oxadiazol-5-yl                                           H         H        3-ethyl-1,3,4-thiadiazol-5-yl                                                                  5,100,893                                 H                  3-(2hydroxy)propyl-                                                                            5,100,893                                                    1,2,4-oxadiazol-5-yl                                       H         H        4-ethyl-3-thiazol-2-yl                                                                         5,100,893                                 H         H        5-ethyl-3-thiazol-2-yl                                                                         5,100,893                                 3-chloro  H        3-ethyl-1,2,4-oxadiazol-5-yl                                                                   5,100,893                                 H         H        4,5-dimethyl-3-thiazol-2-yl                                                                    5,100,893                                 2-methoxy H        4,5dihydro oxazol-2-yl                                                                         4,843,087                                 3-methoxy H        4,5dihydro oxazol-2-yl                                                                         4,843,087                                 3-chloro  H        4,5dihydro oxazol-2-yl                                                                         4,843,087                                 3-hydroxy H        4,5dihydro oxazol-2-yl                                                                         4,843,087                                 3,5 di-t-butyl     4,5dihydro oxazol-2-yl                                                                         4,843,087                                 3-difluoromethyl                                                                        H        4,5dihydro oxazol-2-yl                                                                         4,843,087                                 3-hydroxymethyl                                                                         H        4,5dihydro oxazol-2-yl                                                                         4,843,087                                 3-carboxy H        4,5dihydro oxazol-2-yl                                                                         4,843,087                                 2-methyl  3-hydroxy                                                                              4,5dihydro oxazol-2-yl                                                                         4,843,087                                 2,6 dichloro       4,5dihydro oxazol-2-yl                                                                         4,843,087                                 3,5 difloro        4,5dihydro oxazol-2-yl                                                                         4,843,087                                 3-chloro  5-ethynyl                                                                              4,5dihydro oxazol-2-yl                                                                         4,843,087                                 ______________________________________                                    

BIOLOGICAL PROPERTIES

Biological evaluation of representative compounds of formula I has shownthat they possess antipicornaviral activity. They are useful ininhibiting picornavirus replication in vitro and are primarily activeagainst picornaviruses, including enteroviruses, echovirus and coxsackievirus, especially rhinoviruses. The in vitro testing of therepresentative compounds of the invention against picornaviruses showedthat picornaviral replication was inhibited at minimum inhibitoryconcentrations (MIC) ranging from to micrograms per milliliter (μg/ml).

The MIC values were determined by an automated tissue culture infectiousdose 50% (TCID-50) assay. HeLa cells in monoloyers in 96-well clusterplates were infected with a dilution of picornavirus which had beenshown empirically to produce 80% to 100% cytopathic effect (CPE) in 3days in the absence of drug. The compound to be tested was seriallydiluted through 10, 2-fold cycles and added to the infected cells. Aftera 3 day incubation at 33° C. and 2.5% carbon dioxide, the cells werefixed with a 5% solution of glutaraldehyde followed by staining with a0.25% solution of crystal violet in water. The plates were then rinsed,dried, and the amount of stain remaining in the well (a measure ofintact cells) was quantitated with an optical density reader. The MICwas determined to be the concentration of compound which protected 50%of the cells from picornavirus-induced CPE relative to an untreatedpicornavirus control.

In the above test procedures, representative compounds of formula I weretested against some the serotypes from either a panel of fifteen humanrhinopicornavirus (HRV) serotypes, (noted in the table as panel T)namely, HRV-2, -14, -1A, -1B, -6, -21, -22, -15, -25, -30, -50, -67,-89, -86 and -41 or against some of the serotypes from a panel of 10human rhinopicornavirus serotypes namely HRV-3, -4, -5, -9, -16, -18,-38, -66, -75 and -67, (noted in the table as panel B) and the MICvalue, expressed in micrograms per milliliter (mg/ml), for eachrhinopicornavirus serotype was determined for each picornavirus, examplele is given as an example of the data. Then MIC₅₀ values, which are theminimum concentrations of the compound required to inhibit 50% of thetested serotypes were determined. The compounds tested were found toexhibit antipicornaviral activity against one or more of theseserotypes.

The following Table gives the test results for representative compoundsof the invention. The panel of picornaviruses used in the test appearsbefore the the MIC₈₀ and MIC₅₀ figure and the number of serotypes whichthe compound is tested against (N) is indicated after the MIC₈₀ andMIC₅₀ figure.

                  TABLE                                                           ______________________________________                                        Ex No.   Panel          Mic.sub.50                                                                            N                                             ______________________________________                                         1a      B              3.47    2                                              1c.sub.1                                                                              B              1.27    3                                              1c.sub.2                                                                              T              0.23    9                                              2c      B              0.45    3                                              3       B              0.033   10                                             4       B              --      10                                             5c      T              3.143   3                                              5d      T              5.952   15                                             6c      T              0.153   15                                             7d      T              0.25    14                                             8b      B              0.37    3                                              8c      B              1.1     3                                              8d      B              0.12    7                                              9c      T              --      13                                            10e      T              0.682   13                                            10g      T                                                                    11       B              0.148   10                                            11g                                                                           12d      B              --      5                                             12f      B              0.045   9                                             12g      B              0.125   9                                             12h      B              0.046   8                                             12e      B              0.0945  8                                             13d      B              0.172   9                                             14d      B              0.51    9                                             15c      B              0.71    7                                             15e      B              0.23    9                                             15f      B              0.2     8                                             15g      B              0.47    8                                             18a      T              0.172   13                                            18b      T              0.1225  12                                            18c      T              0.27    15                                            18e      T              2.697   11                                            19       B              0.62    10                                            ______________________________________                                    

Many of the example compounds are quite active. against one or more ofthe serotypes tested, thus the MIC₅₀ is inadequate to describing theirutility. Examples of the biological data follow, MIC₅₀ is listed aftereach serotype.

    ______________________________________                                        Ex.          Serotype (MIC.sub.50)                                            ______________________________________                                        10 F         R6-(0.502)                                                       10 G1        R86-(5.316), R41-(2.186)                                         10 G2        IA                                                               10 G3        IA                                                               10 G4        R15-(2.4734), R30-(0.457)                                        10 G5        IA                                                               16           R1B-(0.186); R21-(0.033); R89-(0.043)                            17 E         R38-(0.341)                                                      17 F         R38-(0.415); R16-(0.714)                                         17 H         R38-(0.449)                                                      18 F         R1B-(0.268); R22-(0.09); R30-(0.071);                                         R50-(0.192); R4-(0.663)                                          19 B         R1B-(0.268); R22-(0.09); R30-(0.071),                                         R50-(0.192); R41-(0.663)                                         ______________________________________                                    

Formulations of the Invention

The compounds of formula I can be formulated into compositions,including sustained release compositions together with one or morenon-toxic physiologically acceptable carriers, adjuvants or vehicleswhich are collectively referred to herein as carriers, in anyconventional form, using conventional formulation techniques forpreparing compositions for treatment of infection or for propylacticuse, using formulations well known to the skilled pharmaceuticalchemist, for parenteral injection or oral or nasal administration, insolid or liquid form, for rectal or topical administration, or the like.

The compositions can be administered to humans and animals eitherorally, rectally, parenterally (intravenous, intramuscularly orsubcutaneously), intracisternally, intravaginally, intraperitoneally,locally (powders, ointments or drops), or as an aerosal, for example asa nasal or a buccal spray.

Compositions suitable for parenteral injection can comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, polyalkylene glycols and the like),suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case of dispersionsand by the use of surfactants.

These compositions can also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents that delay absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, lozenges and granules which may be dissolved slowly inthe mouth, in order to bathe the mouth and associated passages with asolution of the active ingredient. In such solid dosage forms, theactive compound is admixed with at least one inert customary excipient(or carrier) such as sodium citrate or dicalcium phosphate or (a)fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol and silicic acid, (b) binders, as for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia, (c) humectants, as for example, glylcerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates andsodium carbonate, (e) solution retarders, as for example paraffin, (f)absorption accelerators, as, for example, quaternary ammonium compounds,(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate, (h) adsorbents, as, for example, kaolin and bentonite, and(i) lubricants, as, for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate or mixturesthereof. In the case of capsules, tablets and pills, the dosage formscan also comprise buffering agents.

Certain solid dosage forms can be delivered through the inhaling of apowder manually or through a device such as a SPIN-HALER used to deliverdisodium cromoglycate (INTAL). When using the latter device, the powdercan be encapsulated. When employing a liquid composition, the drug canbe delivered through a nebulizer, an aerosol vehicle, or through anydevice which can divide the composition into discrete portions, forexample, a medicine dropper or an atomizer.

Solid compositions of a similar type may also be formulated for use insoft and hard gelatin capsules, using such excipients as lactose or milksugar as well as high molecular weight polyethyleneglycols, and thelike.

Solid dosage forms such as tablets, dragees, capsules, pills andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They can contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Alsosolid formulations can be prepared as a base for liquid formulations. Inaddition to the active compounds, the liquid dosage forms can containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, particularly cottonseed oil, ground-nut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like. Besides suchinert diluents, the composition can also include adjuvants, such aswetting agents, emulsifying and suspending agents, sweetening, flavoringand perfuming agents.

Suspensions, in addition to the active compounds, can contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol, polyethyleneglycols of varying molecular weights and sorbitanesters, microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thepresent invention with suitable non-irritating excipients or carrierssuch as cocoa butter, polyethyleneglycol or a suppository wax, which aresolid at ordinary temperatures but liquid at body temperature and,therefore, melt in the rectum or vaginal cavity and release the activecomponent.

Compositions for administration as aerosols are prepared by dissolving acompound of Formula I in water or a suitable solvent, for example analcohol ether, or other inert solvent, and mixing with a volatilepropellant and placing in a pressurized container having a meteringvalve to release the material in usefule droplet size.

The liquefied propellant employed typically one which has a boilingpoint below ambient temperature at atmospheric pressure. For use incompositions intended to produce aerosols for medicinal use, theliquefied propellant should be non-toxic. Among the suitable liquefiedpropellants which can be employed are the lower alkanes containing up tofive carbon atoms, such as butane and pentane, or a alkyl chloride, suchas methyl, ethyl, or propyl chlorides. Further suitable liquefiedpropellants are the fluorinated and fluorochlorinated alkanes such asare sold under the trademarks "Freon" and "Genetron". Mixtures of theabove mentioned propellants can suitably be employed.

Preferred liquefied propellants are chlorine free propellants, forexample 134a (tetrafluoroethane) and 227c (heptafluoropropane) which canbe used as described above. Typically, one uses a cosolvent, such as anether, alcohol or glycol in such aerosol formulations.

The specifications for unit dosage forms of this invention are dictatedby and directly dependent on (a) the unique characteristics of theactive material and the particular effect to be achieved and (b) thelimitations inherent in the art of compounding such an active materialfor use in humans and animals, as disclosed in detail in thisspecification, these being features of the present invention. Examplesof suitable unit dosage forms in accord with this invention are capsulesadapted for ingestion or, aerosols with metered discharges, segregatedmultiples of any of the foregoing, and other forms as herein described.

Compounds of the invention are useful for the prophylaxis and treatmentof infections of suspected picornaviral etiologies such as asepticmeningitis, upper respiratory tract infection, enterovirus infections,coxsackievirus, enteroviruses and the like. An effective but non-toxicquantity of the compound is employed in treatment. The dosage of thecompound used in treatment depends on the route of administration, e.g.,intra nasal, intra bronchial, and the potency of the particularcompound.

Dosage forms for topical administration include ointments, powders,sprays and inhalants. The active component is admixed under sterileconditions with a physiologically acceptable carrier and anypreservatives, buffers or propellants as may be required. Opthalmicformulations, eye ointments, powders and solutions are alsocontemplated.

It will be appreciated that the starting point for dosage determination,both for prophylaxis and treatment of picornaviral infection, is basedon a plasma level of the compound at roughly the minimum inhibitoryconcentration levels determined for a compound in the laboratory. Forexample a MIC of 1 μg/mL would give a desired starting plasma level of0.1 mg/dl and a dose for the average 70 Kg mammal of roughly 5 mg. It isspecifically contemplated that dosage range may be from 0.01-1000 mg.

Actual dosage levels of the active ingredient in the compositions can bevaried so as to obtain an amount of active ingredient that is effectiveto obtain a desired therapeutic response for a particular compositionand method of administration. The selected dosage level thereforedepends upon the desired therapeutic effect, on the route ofadministration, on the desired duration of treatment and other factorsand is readily determined by those skilled in the art.

The formulation of a pharmaceutical dosage form, including determinationof the appropriate ingredients to employ in formulation anddetermination of appropriate levels of active ingredient to use, so asto achieve the optimum bioavailability and longest blood plasma halflifeand the like, is well within the purview of the skilled artisan, whonormally considers in vivo dose-response relationships when developing apharmaceutical composition for therapeutic use.

Moreover, it will be appreciated that the appropriate dosage to achieveoptimum results of therapy is a matter well within the purview of theskilled artisan who normally considers the dose-response relationshipwhen developing a regimen for therapeutic use. For example the skilledartisan may consider in vitro minimum inhibitory concentrations as aguide to effective plasma levels of the drug. However, this and othermethods are all well within the scope of practice of the skilled artisanwhen developing a pharmaceutical.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the body weight,general health, sex, diet, time and route of administration, rates ofabsorption and excretion, combination with other drugs and the severityof the disease being treated and is readily determined by the skilledclinician.

When administered prior to infection, that is, prophylactically, it ispreferred that the administration be within about 0 to 48 hours prior toinfection of the host animal with the pathogenic picornavirus. Whenadministered therapeutically to inhibit an infection it is preferredthat the administration be within about a day or two after infectionwith the pathogenic virus.

The dosage unit administered will be dependent upon the picornavirus forwhich treatment or prophylaxis is desired, the type of animal involved,its age, health, weight, extent of infection, kind of concurrenttreatment, if any, frequency of treatment and the nature of the effectdesired.

The compound of the invention also finds utility in preventing thespread of picornaviral infection. the compounds can be used in aerosolsprays applied to contaminated surfaces, to disposable products, such astissues and the like used by an infected person. In addition thecompounds can be used to impregnate household products such as tissues,other paper products, disposable swabs, and the like to prevent thespread of infection by inactivating the picornavirus.

Because compounds of the invention are able to suppress the growth ofpicornaviruses when added to a medium in which the picornavirus isgrowing, it is specifically contemplated that compounds of the inventioncan be used in disinfecting solutions, for example in aqueous solutionwith a surfactant, to decontaminate surfaces on which polio, Coxsackie,rhinovirus and/or other picornaviruses are present, such surfacesincluding, but not limited to, hospital glassware, hospital workingsurfaces, restuarant tables, food service working surfaces, bathroomsinks and anywhere else that it is expected that picornaviruses may beharbored.

Hand contact of nasal mucus may be the most important mode of rhinovirustransmission. Sterilization of the hands of people coming into contactwith persons infected with rhinovirus prevents further spread of thedisease. It is contemplated that a compound of the inventionincorporated into a hand washing or hand care procedure or product,inhibits production of rhinovirus and decreases the likelihood of thetransmission of the disease.

We claim:
 1. A compound of formula: ##STR8## wherein Azo isalkyltetrazolyl or is chosen from the group consisting of imidazolyl,pyrazolyl, triazinyl, triazolyl, and oxazolyl, optionally substitutedwith a member of the group consisting of alkyl, alkylthio, alkoxy,hydroxy, halo, cyano, nitro, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl,alkanoyl, fluoroalkyl or the N-oxide of any of the preceding;Y is analkylene bridge of 3-9 carbon atoms; R₁ and R₂ are each individuallychosen from hydrogen, halo, alkyl, alkenyl, amino, alkylthio, hydroxy,hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, alkoxy, nitro, carboxy, alkoxycarbonyl,dialkylaminoalkyl, alkylaminoalkyl, aminoalkyl, difluoromethyl,trifluoromethyl or cyano; R₃ is alkoxycarbonyl, phenyl, alkyltetrazolyl,or a heterocycle chosen from benzoxazolyl, benzathiazolyl, thiadiazolyl,imidazolyl, dihydroimidazolyl oxazolyl, thiazolyl, oxadiazolyl,pyrazolyl, isoxazolyl, isothiazolyl, furyl, triazolyl, thiophenyl,pyridyl pyrimidinyl, pyrazinyl, pyridazinyl or of substituted phenyl orsubstituted heterocyclyl wherein the substitution is with alkyl,alkoxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy,furyl, thienyl or fluoroalkyl; the N-oxide thereof; or apharmaceutically acceptable acid addition salt thereof.
 2. A compoundaccording to claim 1 wherein Y is a linear hydrocarbon chain of 3 toabout five carbons.
 3. A compound according to claim 2 wherein R₃ issubstituted oxadiazolyl or tetrazolyl.
 4. A compound according to claim3 wherein R₃ is chosen from the group consisting of5-trifluoromethyl-1,2,4-oxadiazolyl, 5-fluoromethyl-1,2,4-oxadiazolyl,5-difluoromethyl-1,2,4-oxadiazolyl and 2-methyl-5H-tetrazolyl.
 5. Apharmaceutical composition containing as an active ingredient anantipicornavirally effective amount of a compound according to claim 1.6. A pharmaceutical composition containing as an active ingredient anantipicornavirally effective amount of a compound according to claim 3.7. A pharmaceutical composition containing as an active ingredient anantipicornavirally effective amount of a compound according to claim 4.8. A method of preventing or treating picornaviral infection in amammalian host comprising administering an antipicornavirally effectiveamount of a compound according to claim
 1. 9. A method of preventing ortreating picornaviral infection in a mammalian host comprisingadministering an antipicornavirally effective amount of a compoundaccording to claim
 3. 10. A method of preventing or treatingpicornaviral infection in a mammalian host comprising administering anantipicornavirally effective amount of a compound according to claim 4.11. A method of combating picornaviruses comprising contacting the locusof said viruses with a compound of claim
 1. 12. A method of combatingpicornaviruses comprising contacting the locus of said viruses with acompound of claim
 3. 13. A method of combating picornaviruses comprisingcontacting the locus of said viruses with a compound of claim 5.